Review Article Small-Molecule Hormones: Molecular...

Hindawi Publishing CorporationInternational Journal of EndocrinologyVolume 2013 Article ID 601246 21 pageshttpdxdoiorg1011552013601246

Review ArticleSmall-Molecule Hormones Molecular Mechanisms of Action

Monika Puzianowska-Kuznicka12 Eliza Pawlik-Pachucka12 Magdalena Owczarz2

Monika BudziNska2 and Jacek Polosak1

1 Department of Human Epigenetics Mossakowski Medical Research Centre 5 Pawinskiego Street 02-106 Warsaw Poland2Department of Geriatrics and Gerontology Medical Center of Postgraduate Education 6163 Kleczewska Street01-826 Warsaw Poland

Correspondence should be addressed to Monika Puzianowska-Kuznicka mpuzianowskawumedupl

Received 28 August 2012 Revised 30 December 2012 Accepted 17 January 2013

Academic Editor A L Barkan

Copyright copy 2013 Monika Puzianowska-Kuznicka et al This is an open access article distributed under the Creative CommonsAttribution License which permits unrestricted use distribution and reproduction in any medium provided the original work isproperly cited

Small-molecule hormones play crucial roles in the development and in the maintenance of an adult mammalian organism Onthe molecular level they regulate a plethora of biological pathways Part of their actions depends on their transcription-regulatingproperties exerted by highly specific nuclear receptors which are hormone-dependent transcription factors Nuclear hormonereceptors interact with coactivators corepressors basal transcription factors and other transcription factors in order to modulatethe activity of target genes in a manner that is dependent on tissue age and developmental and pathophysiological states Thebiological effect of this mechanism becomes apparent not earlier than 30ndash60 minutes after hormonal stimulus In addition small-molecule hormones modify the function of the cell by a number of nongenomic mechanisms involving interaction with proteinslocalized in the plasma membrane in the cytoplasm as well as with proteins localized in other cellular membranes and innonnuclear cellular compartments The identity of such proteins is still under investigation however it seems that extranuclearfractions of nuclear hormone receptors commonly serve this function A direct interaction of small-molecule hormones withmembrane phospholipids and with mRNA is also postulated In these mechanisms the reaction to hormonal stimulus appearswithin seconds or minutes

1 Introduction

Molecular mechanisms of action of small-molecule hor-mones have been studied for decadesThe biological functionof these hormones was initially attributed mostly to theirextranuclear activities presently referred to as nongenomichowever the exact mechanisms of such actions were then notknown Subsequently the majority of efforts were directedtowards the clarification of the transcription-modifying func-tion of these hormones bound to their nuclear receptors thatare hormone-regulated transcription factors This generatedan enormous amount of information regarding the genomicaction of hormones the identity of their target genes andso forth It finally became apparent that the genomic actionof hormones is insufficient to fully explain their biologi-cal roles so that the nongenomic mechanisms are againbeing intensively studied In this comprehensive paper wepresent basic information regarding the genomic and nonge-nomic mechanisms of action of small-molecule hormones

emphasizing the intermediary role of various proteinsbetween the hormonal stimulus and the biological responseof the cell It should be noted though that although ourcurrent knowledge of the molecular mechanisms of actionof these hormones is impressive not all has been solved andmany mechanisms still await explanation

2 The Genomic Mechanism of Action ofSmall-Molecule Hormones

ldquoGenomic mechanism of hormone actionrdquo refers to theregulation of target gene activity by hormones via theirprotein receptors which also possess all the features of atranscription factor This mechanism engages transcriptionand translation and its biological effects are executed by anewly synthesized proteins The first effects of engagementof this mechanism might be detected 30ndash60 minutes after itsinitiation howevermaximal effects are usually observed afterseveral hours

2 International Journal of Endocrinology

Table 1 Selected representatives of the nuclear receptor superfamily

Family Receptor LigandI Triiodothyronine receptor (TR) Triiodothyronine

Retinoic acid receptor (RAR) All-trans-retinoic acidVitamin D receptor (VDR) 112057225(OH)2D3

Peroxisome-proliferator-activated receptor (PPAR)Polyunsaturated fatty acids benzopyran eicosanoids15-deoxy-1241-prostaglandin J2 thiazolidinedionesother

Reverse-ErbA (Rev-ErbA) UnknownRetinoic-acid-receptor-related orphan receptor (ROR) UnknownLiver X receptor (LXR) Oxysterols

II 9-cis-Retinoic acid receptor (RXR) 9-cis-Retinoic acidHepatocyte nuclear factor-4 (HNF-4) Acyl-CoA thioesters

III

Estrogen receptor (ER) 17120573-estradiolAndrogen receptor (AR) AndrogensProgesterone receptor (PR) ProgesteroneGlucocorticoid receptor (GR) GlucocorticoidsMineralocorticoid receptor (MR) Mineralocorticoids glucocorticoids

IV Nerve-growth-factor-induced clone-B (NGFI-B) UnknownV Steroidogenic factor-1 (SF-1) OxysterolsVI Germ cell nuclear factor (GCNF) Unknown0 Heterodimerization small partner (HSP) Unknown

21 Nuclear Hormone Receptors Nuclear receptors of small-molecule hormones belong to the superfamily of nuclearreceptors consisting of receptors for steroid hormones thy-roid hormone vitamin D retinoic acid and its derivativesfatty acids prostaglandins and cholesterol derivatives aswell as of ldquoorphanrdquo receptors with unknown ligands Smallfractions of some of these receptors also act outside ofthe nucleus in mechanisms generally called ldquonongenomicrdquowhich are mediated by processes other than a direct bindingof the receptor to DNA

Structural similarities of nuclear receptors allow the sub-division of the superfamily into 7 familiessubfamilies (0ndashVI)families I to VI are quite well defined [56ndash58] while family 0contains various receptors which donot fit into other families(Table 1) Nuclear receptors although recognizing their owntarget genes and ligands with high specificity and being eitherpartly or completely devoid of affinity for other genes andligands have a similar structure (Figure 1) A typical full-length nuclear receptor has a variable AB domain at itsN-terminus followed by a well-conserved DNA-binding Cdomain then by a hinge D domain and by a well-conservedligand-binding E domain Some receptors also have an Fdomain on their C-termini the function of which is usuallyunclear

The AB domain of many nuclear receptors containselements involved in hormone-independent transcriptionactivation (AF1) Its function might be modified by phos-phorylation as was shown for the all-trans-retinoic acidreceptor (RAR) peroxisome-proliferator-activated receptor(PPAR) orphan Nurr1 receptor estrogen receptor (ER) and

so forth [59ndash62] The sequence and tridimensional structureof the C domain determine the recognition specificity ofthe receptorrsquos target genes The domain contains two zincfingers in each of them four perfectly conserved cysteineskeep one zinc ion in place [63] At the base of the firstzinc finger a P-box is present its amino acid sequencedetermines the recognition of a specific (usually hexameric)DNA sequence in the receptorrsquos target genes At the baseof the second zinc finger a D-box is located its sequenceis in turn responsible for the recognition of the distancebetween the two hexamers forming the hormone responseelement (HRE) in the promoter of target gene [64] Inaddition the D-box plays a role in receptor dimerizationThe C domain might contain the nuclear localization signal(NLS) or fragments thereof Next the D domain containsNLS and facilitates rotation of the DNA-binding domain inrelation to the ligand-binding domain In addition it containselements involved in cofactor binding DNA binding andin heterodimerization [65] Finally the E domain binds aspecific hormone takes part in homodimerization as well asin heterodimerization and on its C-terminal end containsa ligand-dependent transcription activation domain (AF2)[66] In some cases the E domain might play a role in theactive inhibition of transcriptionThe E domain of the steroidhormone receptors takes part in the binding of heat shockproteins (HSP chaperone) The structure of this domain isformed by 12 120572-helices (H1ndashH12) and resembles pocket-likehormone-binding site The sizes shapes and charges of thispocket present in various receptors differ from each otherand this why most receptors bind only their own hormones

International Journal of Endocrinology 3

AB C D E

DBD

H

DD DD

NLSNLS

AF1

AF2

AR

DNA-binding domain

Hormone-binding domain

Dimerization domain

Nuclear localization signal

Hormone-independent transcription activation domain

Hormone-dependent transcription activation domain

Active repression domain

F

Figure 1 Schematic diagram of nuclear hormone receptor structure

with an extremely high specificity and affinity howeversome of them such as the PPAR120574 receptor possesses a largepocket allowing them to bind various ligands [67] A veryimportant feature of nuclear receptors is that in the absenceof the hormone conformation of their E domains differsfrom that acquired upon hormone binding [68ndash70] Themost spectacular is the change of position of the last helix(H12) containing the AF2 domain Without the hormonethe H12 is moved to the side and protrudes from the restof the E domain leaving the empty pocket opened Uponhormone binding the H12 comes nearer and closes thehormone inside the pocket [71] This feature is crucial forthe majority of the functions of nuclear hormone receptorsincluding subcellular localization (as for steroid receptors)and transactivation activity

The activity of the nuclear receptor might be modulatedby various posttranscriptional modifications including phos-phorylation acetylation methylation palmitoylation andsumoylation [72ndash76] In addition its biological efficiencydepends on the rate of its turnover [77] Like many otherproteins hormone receptors are degraded mainly by theubiquitin-proteasome-dependent pathway To be degradedby the proteasome proteins must be tagged with multipleubiquitinsThe process of tagging depends on three enzymesacting sequentially the third one ubiquitin ligase deter-mines the specificity of protein ubiquitylation [78] for exam-ple Hdm2 and carboxyl-terminal HSP70 interacting protein(CHIP) promote degradation of the glucocorticoid receptor(GR) [79 80] Blocking receptor degradation by protea-some inhibitors impairs ER120572- and progesterone-receptor-(PR-) mediated transactivation but enhances GR-mediatedtransactivation [81 82] Notably binding of chaperones suchas HSPs and associated proteins to steroid hormone receptorprevents receptor ubiquitylation [83 84] Calmodulin (CaM)binding to ER120572 also prevents receptor ubiquitylation anddegradation by the proteasome [85 86] while its bindingto AR prevents receptor degradation by calpain [87] Inaddition palmitoylation of ER120572 decreases 17120573-estradiol-dependent receptor degradation [88]

22 Hormone Response Elements in the Promoters of TargetGenes A classic genomic mechanism of action of small-molecule hormones is based on the binding of its nuclear

receptor to the target gene Two elements facilitate such aninteraction the DNA-binding domain of the receptor andHRE a specific sequence in the regulatory elements of thegene Such sequences (single ormultiple) are usually localizedclose to the basal promoter not farther than several hundredbase pairs in the 51015840 direction from the transcription startsite (TSS) However they might also be present in atypicalpositions for example in the enhancers localized even afew thousand base pairs above the TSS The negative HREs(nHREs) tend to localize close to TSS sometimes even belowthis site [89 90]

Analysis of the natural and artificial HREs showed thatnuclear hormone receptors preferentially recognize hexam-ers sequences consisting of six nucleotides Steroid hormonenuclear receptors (family III) with the exception of ERpreferentially bind to the AGAACA sequence while theremaining receptors including families I and II receptorsand ER prefer the GAGGTCGA sequence [91ndash93] Bothare consensus sequences and consist of the nucleotides mostcommonly found at a given position in natural HREs itis then to be expected that natural HREs very commonlydiffer from the consensus sequence HREs usually are formedby two hexamers and most commonly nuclear hormonereceptors bind to the DNA either as homodimers (mostlybut not exclusively family III receptors) or as heterodimers(mostly families I and II receptors) [94ndash99] The bindingof a monomeric receptor to a monomeric or to a dimericHRE is plausible as in the case of steroidogenic factor-1 (SF-1 family V) [100] but for ldquoclassicrdquo receptors such situationsare less common Depending on the relative position of thetwo hexamers dimeric HRE might be a direct repeat (DR)palindromic (PAL) or inverted palindrome (IP) HRE

HREs for steroid hormone receptors also called steroidhormone response elements (SREs) are usually palindromesconsisting of the AGAACAnnnTGTTCT or of a simi-lar sequences with three neutral (eg of any sequence)nucleotides between hexamers As mentioned above theexception to this rule is ER which preferentially binds tothe GAGGTCGAnnnTCGACCTC palindrome [64 101]Nevertheless each of these receptors preferentially recog-nizes its own target SREs with a very high specificity beinga result of various factors such as deviations from the SREconsensus sequence distinct amino acids surrounding DNA


binding domain fragments of the receptor directly contactingSRE interactions with other transcription factors bound totheir own binding sites in the proximity of SRE tissue-specific expression of various receptor isoforms and the levelof receptor expression [102 103] It should be mentioned thatother types of SREs are known such as a selective androgenresponse element (ARE)which is not PAL butDR-type It hasbeen recently shown that such AREsmight be recognized notonly by AR but also by PR [104 105] In addition to classicSREs which mediate transcription activation a number ofnegative SREs are known that inhibit the transcription whenthe steroid-hormone-activated receptor binds to nSRE [106107]

Nuclear receptors belonging to the families I and IIpreferentially bind to the consensusGAGGTCGA sequenceorganized into DR PAL or IP [108ndash111] The binding toDR drives the strongest biological effect in fact naturalHREs recognized by these receptors are most commonlyDRs Specificity of the binding is achieved thanks to HRErsquosconfiguration to the number of neutral nucleotides sepa-rating the two hexamers to the sequence of hexamers andof HRE-flanking DNA-fragments and to the sequence ofthe receptor DNA-binding domain [112ndash115] In DRs oneneutral nucleotide between hexamers (DR1) warrants thebinding of RXRRXR homodimers of RARRXR or ofPPARRXR heterodimers two nucleotides (DR2)mdashthe bind-ing of RARRXR heterodimer three nucleotides (DR3)mdashthe binding of VDRRXR heterodimer four nucleotides(DR4)mdashthe binding of TRRXR heterodimer finally fivenucleotides (DR5) ndash the binding of RARRXR heterodimerNuclear receptors for nonsteroid small-molecule hormonesalso bind to DR0 and to DRs with more than five neutralnucleotides separating hexamers [116 117] as well as to othernonclassical HREs In addition some HREs might be boundby various receptors for example the AGGTCATGACCTPAL0 sequence is recognized by TR- VDR- and RAR-containing dimers [118ndash120] Specific nHREs are also knownfor practically all nuclear hormone receptors belonging to thefamilies I and II [121ndash124]

In addition nuclear hormone receptors might bind asmonomers to a single hexamer preceded by an A- and T-richsequence as shown for Rev-ErbA retinoic-acid-receptor-related orphan receptor-120572 (ROR120572) and for nerve-growth-factor-induced clone B (NGFI-B) orphan receptors [100 125126]

23 Regulation of Transcription On the basis of the molec-ular mechanism of action and of the subcellular localizationin the absence of ligand nuclear hormone receptors can bedivided into two types In general type I receptors prefer-entially reside in the cytoplasm (in unliganded form) andwhile in the nucleus aremost active as homodimersThe bestknown receptors of this type are family III steroid hormonereceptors Type II receptors after being synthesized andmodified in the cytoplasm in the presence or absence of theirligand preferentially translocate to the nucleus where theyare most active as heterodimers The best known receptorsof this type belong to families I and II Binding of nuclearhormone receptors to DNA might result in transcription

Tran

scrip

tiona

l act

ivity

Basaltranscriptionalactivity

+HRminusH

+HR +HRminusH

+HRminusHRminus+H

Genes positivelyregulated

Genes negativelyregulated

+H +H

Figure 2 Diagram of transcription regulation by small-moleculehormones H hormone HR nuclear hormone receptor

activation or in transcription inhibition and such phenom-ena result from variable molecular mechanisms Each hor-mone has a group of target genes which it activates (positivelyregulated genes) and a group of genes which it inhibits(negatively activated genes) (Figure 2)

231 Type I Receptors In the circulation steroid hormonesare bound to transporting proteins They enter the cell bydiffusion or are actively transported by a cell-membrane-bound transporting proteins The majority of their nuclearreceptors a classic examples of type I receptors reside in thecytoplasm forming inactive complexes with various proteinsincluding heat shock proteins HSP70 and HSP90 Formationof such complexes promotes proper folding of the receptorinto a conformation allowing steroid binding [127ndash131] Uponhormone binding receptor conformation changes and thisresults in the breakup of the complexThe ldquoactivatedrdquo receptortranslocates to the nucleus thanks to its association withchaperones and importins [132 133] where it binds to its SREsin the promoters of target genes (Figure 3) It is suggested thatintranuclear mobility of steroid receptors some of the mostmobile proteins within the nucleus depends on the presenceof chaperone proteins such as HSP90 [134]

Steroid hormone receptors usually bind to DNA ashomodimers Their preferential SREs are palindromes sepa-rated by three neutral nucleotides Occasionally they mightbind to DNA as monomers in such a case SRE might consistof only one hexamer and is usually preceded by an A- andT-rich sequence Binding of the steroid hormone receptorto SRE initiates recruitment of a multiprotein coactivatorcomplex which by modification of chromatin structure (eghistone acetylation by histone acetyltransferases HATs) andby interaction with the basal transcriptional machinery acti-vates transcription [135ndash140] (Figure 3) In addition steroidhormones acting by their nuclear receptors can potentiate thetransactivatory function of other transcription factors [141ndash143]


HRE

CoABTF

RNA Pol II

SH

HR

SH

SH

HR

HRHSP

HSP

SHSH

SH

HAT

R

HR

Figure 3 Diagram of type I receptor genomic mode of action In the circulation the majority of the hormones form complexes withtransporting proteinsThe hormone enters the cell by diffusion or is actively transported by specific cell membrane proteins In the cytoplasmhormone-free receptors form an inactive complex with heat shock chaperone proteins Upon hormone binding the receptor changes itsconformation dissociates from the complex and translocates into the nucleus Hormone-activated receptors bind to HREs as homodimersRecruitment of a coactivator complex possessing a histone acetyltransferase activity results in local chromatin decondensation and increasesthe accessibility of the promoter for transcription factor As a result transcription increases SH steroid hormone HR nuclear hormonereceptor HSP heat shock protein HRE hormone response element CoA coactivator complex HAT histone acetyltransferase BTF basaltranscription factors RNA Pol II type II RNA polymerase and R ribosome

Inhibition of transcription by steroid hormones andtheir receptors is a result of a variety of mechanismssuch as hormone-receptor-complex-dependent inhibition ofthe activity of other transactivators for example activatorprotein 1 (AP1) and NF-120581B [144ndash146] In this mechanismbinding of the receptor to DNA is not necessary A number ofnSREs are also known Binding of a hormone-activated or ahormone-free steroid receptor to nSRE leads to the inhibitionof transcription mediated either by corepressors bound tohormone-activated receptor or by another group of corepres-sors bound to hormone-free receptor Such interaction resultsin deacetylation of histones exerted by histone deacetylases(HDACs) and in modification of chromatin structure Inturn chromatin becomes condensed and inaccessible totranscriptional activators [147ndash151] Other molecular mech-anisms involved in the inhibition of gene transcription vianSRE are also known such as competition for a binding sitewith transcriptional activators [107 152ndash154]

232 Type II Receptors Families I and II receptor proteinssynthesized and modified in the cytoplasm have their NLSexposed so they can translocate to the nucleus in the absenceof the hormoneTherefore both hormone-free and hormone-bound forms of the receptor could be present in the nucleusSince the conformation of the DNA-binding D domain isstable (independent of the hormone) both receptor formsmight bind to the promoter of the target gene this is whytype II receptors are able either to activate or to inhibittranscription of the same gene in a hormone-dependentmanner

In contrast to type I receptors type II receptors usuallybind to their HREs as heterodimers Their universal het-erodimerization partner is RXR Heterodimerization with

RXR modulates nuclear trafficking of other receptors [155156] and increases both affinity of the other receptor to itsHRE as well as its transactivation activity [157ndash160] Type IIreceptors can also bind to DNA as heterodimers with nuclearreceptors other than RXR as homodimers and as monomers[111 161ndash163] In such a case their affinity for DNA might belower than that of heterodimers with RXR

It should be remembered that type II receptors preferen-tially recognize HREs consisting of two hexamers creatingDR PAL and IP In VDR TR and RAR heterodimerswith RXR which bind to DR3 DR4 and DR5 respectivelyRXR preferentially binds to the first hexamer [164 165] Onthe other hand in RARRXR and PPARRXR heterodimersbound to DR1 RXR occupies the second hexamer [166 167]The presence of RXR in receptor heterodimers raises thequestion as to how 9-cis-retinoic acid modifies transcriptionof other hormonesrsquo target genes Most probably it has noinfluence on the level of activation of triiodothyronine (T3)target genes bound by TRRXR and of 112057225(OH)

2D3 target

genes bound by VDRRXR [168 169] however there arereports claiming otherwise [170] In all-trans-retinoic acidtarget genes bound by the RXRRAR heterodimer 9-cis-retinoic acid alone does not regulate the activity of suchgenes but when both receptors are simultaneously boundto their ligands (9-cis-retinoic acid and all-trans retinoicacid respectively) genes are activated synergistically [171]Finally when RXR forms heterodimers with a ldquopermissiverdquopartner such as PPAR liver X receptor (LXR) or nerve-growth-factor-induced B (NGFI-B) orphan receptor 9-cisretinoic acid can regulate transcription on its own or actsynergistically with the ligand of its partner [172 173]

In addition to HREs mentioned above type II receptorsbind to numerous untypical HREs and to very common


HRE

CoRRXR HR

HDAC

HR

R

TF

(a)

HRE

CoABTF

RNA Pol II

HRXRHR

HH

H

HHR

HAT

R

(b)

Figure 4 Diagram of type II receptor genomic mode of action (a) In the absence of the hormone the receptor binds to HRE as heterodimerwith 9-cis-retinoic acid receptor The hormone-free receptor recruits a corepressor complex possessing a histone deacetylase activityDeacetylation of histones results in chromatin condensation and in transcription inhibition (b) In the circulation the hormone formscomplexes with transporting proteins The hormone enters the cell by diffusion or is actively transported by specific cell membrane proteinsThe majority of type II receptors reside in the nucleus Upon hormone binding the receptor changes its conformation which results in thedissociation of the corepressor complex and in the binding of the coactivator complex Histone acetylation by HDAC results in chromatindecondensation which promotes transcription factor binding to DNA and transcription activation H hormone RH nuclear hormonereceptor RXR 9-cis-retinoic acid receptor HRE hormone response element CoA coactivator complex HAT histone actyltransferaseCoR corepressor complex HDAC histone deacetylase TF transcription factor BTF basal transcription factors RNA Pol II type II RNApolymerase and R ribosome

nHREs Binding of the hormone-receptor complex to nHREresults in transcription inhibition so that the recruitmentof corepressors preferentially binding to hormone-activatedreceptor plays here a major role

Hormone target genes with unoccupied HREs are activeon the basal level which depends on the presence of tran-scription factors other than hormone receptors In genes pos-itively regulated by the hormone the binding of a hormone-free receptor heterodimer to HRE leads to the recruitment ofa corepressor complex which by deacetylation of histonesleads to condensation of chromatin This in turn hampersthe binding of transactivators and of basal transcriptionfactors to DNA as a result transcription is inhibited belowthe basal level (Figure 4(a)) [147 148 174ndash176] Howeverupon hormone binding to the receptor conformation of itsligand-binding domain changes this results in the dissoci-ation of corepressors in the recruitment of a coactivatorcomplex containing HATs and in transcription activationmarkedly above the basal level (Figure 5(b)) [177ndash189] Ingenes negatively regulated by the hormone transcriptioninhibition occurs as a result of numerous mechanisms someof them are still not completely known The inhibition couldbe indirect depending on the binding of hormone receptorsto a strong transactivator (such as AP1 NF-120581B and p53) suchbinding results either in a blockage of transactivatorrsquos activityor in its binding to DNA [190ndash192] In this mechanism thebinding of the receptor to the DNA is not a prerequisite forthe inhibition of transcription In the direct mechanismsHRE might be present close to or might overlap the bindingsite for a strong transactivator Under such circumstancestranscription inhibition is the result either of competitionfor a binding site or of binding of the receptor to thetransactivator resulting in the repression of its activity [193

194] In another direct mechanism the binding of hormone-activated receptor to nHRE initiates recruitment of spe-cific corepressors preferentially recognizing hormone-boundreceptors [149ndash151 195ndash198] In addition hormonal receptorsbound to nHREs located close to (commonly behind) thetranscription start sitemight affect the binding of type II RNApolymerase to the basal promoter [199]

233 Interaction of Nuclear Hormone Receptors with OtherProteins Asmentioned above the biological action of small-molecule hormones depends on their interaction with theirreceptors as well as on the interactions of the receptor withDNA and with other proteins In the genomic mechanismof hormone action the most important interaction is thatof the receptor with coactivators corepressors and othertranscription factors On the other hand in the nongenomicmechanisms the most crucial role is played by the bindingeither of the cytoplasmic fraction of nuclear receptors or ofhormone itself to extranuclear proteins

Interaction of Nuclear Hormone Receptors with Basal Tran-scription Factors Transcription may occur only in the pres-ence of basal transcriptionalmachinery a complex consistingof tens of proteins bound to DNA close to the transcriptionstart site A typical basal promoter contains a TATA box(TATAATAAT) located 20ndash30 base pairs above TSS asequence recognized by TATA-binding protein (TBP) Somepromoters do not have this sequence however the basaltranscriptional machinery binds to such promoters anywayand at a similar distance form TSS as in the case oftypical promoters Binding of TBP to the basal promoterinitiates a cascade of binding of other basal transcriptionfactors TBP together with TBP-binding proteins (TAFs)


H

CoA

HAT RNA Pol IIBTF

HRE TATA

HRHR

p160 p300CBPpCAFLXXLL

(a)

CoR

HRE

HR HR

NCoR SMRT

HDAC

CoRNR

(b)

CoR

HDAC

nHRE

HHR HR

RIP140LCoRHrLXXLL

(c)

Figure 5 Coactivators corepressors chromatin and regulation of transcription (a) The coactivator complex consists of many proteinsincluding proteins with the LXXL (L leucine X any amino acid) motif by which they bind to the hormone-activated nuclear receptorHistone acetyltransferase activity might be presented by more than one protein of this complex Decondensation of the chromatin structureupon histone acetylation and a direct interaction of the coactivator complex with basal transcription factors result in transcription activation(b) In the absence of the hormone receptor conformation promotes the binding of a multiprotein corepressor complex Binding of thereceptor to this complex occurs by the LXXIHIXXXIL (L leucine X any amino acid I isoleucine and H histidine) motif present in acorepressor proteinThe complex includes class I or class II histone deacetylase Histone deacetylation leads to the condensation of chromatinand as a result limits the access of transcription factors to the DNA As a result transcription is inhibited (c) Some corepressor proteinscontain the LXXL motif and preferentially bind to the receptors activated by the hormone Next by the recruitment of the corepressorcomplex including histone deacetylase they stabilize tight chromatin structure and repress transcription H hormone HR nuclear hormonereceptor HRE hormone response element nHRE negative hormone response element CoA corepressor complex p160 p300CBP andpCAF coactivator proteins LXXL coactivator protein motif involved in receptor binding HAT histone acetyltransferase CoR corepressorcomplex NCoRSMRT classic corepressor complexes CoRNR LXXIHIXXXIL corepressor protein motif involved in receptor bindingHDAC histone deacetylase RIP140LCoRHr nonclassical corepressor proteins preferentially binding to hormone-activated receptors BTFbasal transcription factors and RNA Pol II type II RNA polymerase

forms transcription factor IID (TFIID) The next step ofpreinitiation complex formation is the binding of IIB (TFIIB)IIF (TFIIF) and IIH (TFIIH) transcription factors Finallytype II RNA polymerase is bound and transcription isinitiated Nuclear hormone receptors interact with the basaltranscription factors not only via other proteins (coactivatorsand corepressors) but also interact with them directly It hasbeen shown that TR RXR RAR ER GR and androgenreceptor (AR) might directly bind to TBP AR and ERmdashtoTFIIF ER TR and VDRmdashto TFIIB and so forth [200ndash205]It is suggested that such binding might bidirectionally affect(activate or inhibit) the recruitment of the basal transcriptionfactors to the preinitiation complex

Interaction of Nuclear Hormone Receptors with CoactivatorsTransfer of information regarding binding of the receptorto HRE and the receptor status (hormone-free or hormone-bound) to the basal transcriptional machinery is usuallyexecuted by other proteins that do not bind to DNA but forma functional ldquobridgerdquo Such proteins possess various activitiesThe same coactivator or corepressor complex might bind toseveral nuclear receptors some of these complexesmight also

coregulate transcription initiated by transcription factors ofother type

The first coactivator cloned in humans was steroid recep-tor coactivator-1 (SRC-1) [179] Together with TIF-2 (SRC-2)and TRAM-1 (SRC-3 ACTR and RAC3) it forms the p160coactivator family The p160 proteins are indeed coactivatorsof many nuclear receptors including GR ER PR VDR TRRXR and PPAR [179 180 183 189] They contain an LXXLL(L leucine X any amino acid) motif by which they bind tothe ligand-binding domain of the receptor activated by thehormone Importantly a specific structure of the receptorfirst of all of its AF2 domain is a prerequisite for suchinteraction [206]

CREB-binding protein (CBP) and p300 possess a histoneacetyltransferase activity [207 208] and are coactivators ofvarious transcription factors including nuclear hormonereceptors [177 178] The binding of p300CBP to the nuclearreceptor is hormone dependent and AF2 domain dependentp300CBP bind to p160 proteins to TBP and to TFIIB basaltranscription factors and as such are intermediates betweenreceptors and basal transcriptionalmachinery Another coac-tivator p300CBP-associated factor (pCAF) interacts with


p160 p300CBP and hormonal nuclear receptors It also hasa histone acetyltransferase activity [182]

Multiprotein complexes containing thyroid-hormone-receptor-associated proteins (TRAP) or vitamin-D-receptor-interacting proteins (DRIP) have been identified [181 185]Both complexes are very similar if not identical and consistsof fourteen-sixteen 70ndash230 kDa proteins Their DRIP205TRAP220TRIP2 subunit by the LXXLLmotif interacts withTR VDR and other nuclear receptors such as RXR and RAR[209] in a hormone-dependent and a receptor-AF2-domain-dependent manner Other components of these complexesinteract with the basal transcriptional machinery

A number of other coactivators interacting with nuclearreceptors are known such as PPAR120574 coactivator 1 (PGC-1)which also interact with other receptors for example withTR [184 188] and with activating signal cointegrators-1 and -2 (ASC-1 andASC-2) interactingwith SRC-1 p300CBP basaltranscription factors and nuclear receptors [186 187]

The formation of a coactivator complex is initiated bythe binding of hormone-bound receptor to its HRE This isfollowed by the recruitment of the coactivator proteins whichdirectly bind nuclear receptors and by the binding of otherproteinsThefinalmulticomponent complex bymodificationof chromatin structure and by interaction with the basaltranscriptional machinery activates transcription of targetgenes

Interaction of Nuclear Hormone Receptors with CorepressorsInhibition of transcription is usually achieved by the interac-tion of the receptor with corepressors [176] The best knowncorepressors are nuclear corepressor (NCoR RIP-13) a large270 kDa protein as well as silencing mediator for retinoicacid and thyroid hormone receptors (SMRT) [147 148] Bothproteins have several isoforms Other proteins such as thesmall ubiquitous nuclear corepressor (SUN-CoR) and theAlien protein might also serve as nuclear hormone receptorcorepressors [174 175] The motif that allows NCoR andSMRT to bind to the receptor is LXXIHIXXXIL (L leucineX any amino acid I isoleucine and H histidine) [210 211]NCoR and SMRT bind to the families I and II nuclearreceptors to ER and to PR (but not to other members offamily III) bound to a specific antagonists and to someorphan receptors They also bind to other proteins includingHDACs [212 213]

Recent developments identified a heterogeneous group ofcorepressors of a new type What makes them unique amongcorepressors is the fact that they bind to the receptor activatedby the hormoneThegroup includes receptor-interacting pro-tein 140 (RIP140) and ligand-dependent corepressor (LCoR)They bind to a various ligand-bound receptors including ERGR PR and VDR via the coactivator-specific LXXLL motifbut recruit HDAC proteins and other corepressors [149ndash151]

Hairless protein (Hr) contains both the hormone-activated-receptor-binding LXXLL motif and a CoRNRboxmdasha sequence mediating the binding of the corepressorto the hormone receptor When it interacts with ligand-bound ROR it utilizes the LXXLL motif whereas when itinteracts with VDR it likely utilizes another domain On theother hand Hr interacts with hormone-free TR as a typical

corepressor utilizing the CoRNR box and recruiting HDAC[195ndash197]

The preferentially expressed antigen in melanoma(PRAME) is expressed in various cancers but in healthytissues it is present only in testes ovaries endometriumand adrenal glands PRAME contains the LXXLL motif andselectively inhibits transcription in the presence of all all-trans-retinoic-acid-bound RAR isoforms It likely executesthis inhibition by recruiting other corepressors [198]

The repressor of estrogen activity (REA) binds to the ER-agonist (eg 17120573-estradiol) and to the ER-antagonist (egtamoxifen) complexes By doing so in the presence of agonistit inhibits the activity of target gene while in the presenceof antagonist it magnifies its action [214] The suppressionby REA is a result of the competition with coactivators forbinding to ER as well as of the recruitment of HDAC and ofchromatin modification

Metastasis-associated factor 1 (MTA1) is another core-pressor preferentially binding to a ligand-activated ER [215]It inhibits the expression of estrogen target genes by com-peting with coactivators for the binding to the receptor byrecruiting HDAC and by chromatin modification

A group of corepressors that might bind both ligandedand nonliganded hormone receptors is also known Forexample the NR-binding SET domain containing protein 1(NSD1) possesses separate domains one that binds hormone-free receptors TR and RAR (NIDminusL) and another that bindshormone-bound TR RXR ER and RAR receptors (NID+L)[216]

Interaction of Hormonal Nuclear Receptors with Other Tran-scription Factors Natural HREs are located relatively closeto TSS or in more distant regulatory elements and bind-ing sites for other transcription factors are usually locatednearby Such proximity permits interaction between nuclearreceptors and these transcription factors leading either tothe suppression of gene activity (as described above) or toits additive or synergistic activation The binding of nuclearreceptors to other transcription factors might also occur ina DNA-binding-independent manner In fact the binding ofall known nuclear hormone receptors to the transcriptionfactors has been reported the best known examples are thebinding of TR to p53 GR and PR to Oct-1 GR to AP-1 and toNF-120581B PPAR to NF-120581B AP-1 and to STAT [217ndash221]

234 Nuclear Hormone Receptors and Chromatin A nucle-osome consists of eight histone molecules (two of eachH2A H2B H3 and H4) Their N-terminal ends (tails)protrude from the compact nucleosome body Epigeneticmodifications of amino acids forming such tails play amarked role in chromatin organization Increased acetylationrelieves compact chromatin which results in an exposureof the transcription-factor-binding sites and their increasedaccessibility leading to transcription activation On the otherhand deacetylation of histone tails leads to the formationof a compact chromatin As a result transcription-factor-binding sites become inaccessible to transactivators and thegene becomes transcriptionally inactive Such a mechanismof modification of chromatin structure is utilized by nuclear


B

mtDNAHRE

MAPKactivation

AKTactivationp110

PI3K

BTFTFTFRNA Pol II

p28

HHR

HHRHR

HHRH Ca2+

PKAactivation

PKCactivation

IP3

PLC

cAMP

RASMEKERKactivation

A

C

D

E

F

P PP Cytoplasmic

effects

c-SRC

H

H

p85

AC

HR

HR

120572

H

Figure 6 Simplified diagram of nongenomic mechanisms of action of small-molecule hormones All nongenomic mechanisms activatenumerous transduction pathways and by a series of phosphorylation events of cytoplasmic and of nuclear proteins modify cell function(A) Interaction of the hormone with either cell membrane receptor or directly with membrane phospholipids modifies the function ofion channels (B) Activation of phospholipase (C) initiated by the hormone-activated cell membrane receptor and of adenylate cyclase(and most possibly of other enzymes) stimulates production of secondary messengers (C) Activation of c-SRC by the hormone-activatednuclear receptor (D) The binding of the hormone-activated nuclear receptor to the phosphatidylinositol 3 kinase p85120572 subunit activatesthis enzyme and results in an increased synthesis of inositol triphosphate (E) In mitochondria small-molecule hormones acting via theirnuclear receptors or by their shorter (mitochondrial) isoforms regulate transcription of mitochondrial DNA In addition interaction ofsome hormones alone or of hormone-receptor complexes with mitochondrial proteins stimulates thermogenesis (F) The binding of thehormone activates protein kinase (C) HR various types of hormone receptors Ca2+ calcium ion p85120572 p110 phosphatidylinositol 3 kinasesubunits PI3K phosphatidylinositol 3 kinase IP3 inositol triphosphate PLC phospholipase (C) AC adenylate cyclase cAMP cyclic AMPAKT protein kinase (B) c-SRC tyrosine kinase PKA protein kinase (A) PKC protein kinase (C) MAPK mitogen-activated proteinkinase RASMEKERK protein kinases p28 shortest isoform of TR120572 mtDNA mitochondrial DNA HRE hormone response elementTF transcription factor BTF basal transcription factors and RNA Pol II type II RNA polymerase

hormone receptors which as mentioned above interactwith coactivators and corepressors p160 and p300CBPcoactivators themselves possess HAT activity and formcomplexes with other HAT proteins such as pCAF Onthe other hand corepressor proteins recruit class I andclass II HDAC proteins to the corepressor complex Thebinding of a ligand-activated receptor to HRE initiates theformation of a coactivator complex which thanks to theHAT activity increases histone acetylation and induces localdecondensation of chromatin (Figure 5(a)) On the otherhand the binding of a hormone-free receptor toHRE initiatesthe formation of a corepressor complex which thanks toits HDAC activity induces local condensation of chromatin(Figure 5(b)) Finally the corepressor complex and its HDACactivity are utilized by the specific corepressor proteinsdescribed above which bind to a hormone-activated receptorand inhibit transcription of the target gene (Figure 5(c))

3 The Nongenomic Mechanisms of Action ofSmall-Molecule Hormones

Fast biological effects of hormones just seconds or minutesafter hormone administration have already been describedseveral dozen years ago The rapidity of biological response

and its independence from transcription and from trans-lation suggested that the genomic mechanism of hormoneaction is not involved therefore this mechanism was callednongenomic or extragenomicThe nongenomic mechanismsof hormone action are multiple variable and only partiallyknown (Figure 6)

31 Nongenomic Mechanisms of Hormone Action Induced bythe Interaction of Hormones with Membrane and CytoplasmicReceptors Steroid and nonsteroid small-molecule hormonesbind to various proteins localized outside the nucleus andactivate transduction pathways leading to a fast biologicalresponse The presence of binding sites in the cell membranewas proved for all major representatives of these hormoneshowever in many cases the identity of the binding proteinremains unknown In addition it is likely that such hormoneshave more than one type of membrane receptors In the caseof receptors already identified their mode of action is by andlarge only partially resolved

Just next to the cell membrane or directly in it usuallywithin caveolae (a bubble-like 50ndash100 nm invaginations ofthe cell membrane) proteins identical to the nuclear recep-tors for glucocorticoids estrogen androgen and vitaminD have been identified [222ndash225] It is then plausible that


nuclear receptors of other small-molecule hormones arepresent close to or in the cell membrane Some small-molecule hormones bind to other than nuclear receptor-likecell membrane proteins For example the integrin receptor120572V1205733 plays a role of cell membrane receptor for thyroxin(T4) [226] mPR120572 mPR120573 mPR120574 mPR120575 and mPR120576 cellmembrane receptors for progesterone possess seven trans-membrane domains (some authors even suggest the presenceof eight such domains) and interact with G proteins [227228] The G-protein-interacting cell membrane receptor forsteroid-hormone-binding protein (SHBG) binds androgenswith higher and estrogenswith lower affinityTheprerequisitefor signal transduction from the hormone to the cell interiorby this receptor is the binding of a hormone-free SHBG firstfollowed by hormone binding [229 230] 120574-Aminobutyricacid A (GABAA) receptor serves as the cell membranereceptor for neurosteroids [231]

311 Nuclear Hormone Receptor Targeting at the MembraneThebest studied ismembrane targeting of ER It is induced bypalmitoylation of cysteine 447 [232] a modification increas-ing protein hydrophobicity and therefore facilitating proteinassociation with lipid bilayer Truncated 46 kDa variant ofER120572 is preferentially palmitoylated and enriched in the cellmembranes [233] it is suggested that it might be more activethan full-length receptor [234] Anothermembrane-localizedvariant of ER120572 ER120572-36 is also functionally active [235]Palmitoylation of ER is promoted by HSP27 [236]

Enzymes identified as palmitoylacyltransferases for sexhormone receptors are DHHC-7 and DHHC-21 proteins[237] A highly conserved 9-amino acidmotif (FVCLKSIIL inER120572) that is crucial for palmitoylation and membrane local-ization has been identified in the ligand-binding domainsof ER120572 ER120573 PR120572 PR120573 GR and AR [238] TR120572 and TR120573possess a motif (LPCEDQIIL) that slightly differs from theone described above but presumably it is also involved in thereceptor palmitoylation and membrane targeting NotablyMR PPARs and RAR do not have any sequence resemblingthis motif [238]

Translocation of nuclear hormone receptors to the mem-brane is also induced in the presence of the respective ligandthis was shown for ER120572- and 17120573-estradiol [239] and for VDRand 112057225(OH)

2D3 [240]

In the cell membrane nuclear hormone receptors interactwith caveolae-specific proteins for example ER120572 and ARphysically interact with Caveolin-1 [234 241] while VDRbinds to Caveolin-3 [242] Binding to caveolins is required formembrane localization of the receptor [234] Furthermorebinding to caveolins allows hormone receptors to initiate fastspecific nongenomic response to hormonal stimulus

312 Induction of Transduction Pathways Upon bindingto the cell membrane receptors small-molecule hormonesactivate various transduction pathways by a receptor-type-dependent mechanism By activation of phospholipase C(PLC) and generation of the secondary messenger inositol145-trisphosphate (IP3) they might activate the cell mem-brane and the sarcoplasmic reticulum (the most impor-tant Ca2+ storage) ion channels Such activation leads to

the increase of intracellular concentration of Ca2+ anothersecondary messenger crucial for many cellular functionsCa2+ activates among others RASRAFMEKERK kinasesprotein kinase C (PKC) and protein kinase A (PKA) As aresult activated kinases phosphorylate and activate numer-ous cytoplasmic and nuclear proteins including hormonalreceptors transcription factors and coactivators This inturnmodulates various biological processes in the cytoplasmand influences transcription of genes regulated by newlyphosphorylated hormone receptors and transcription factorsCell-membrane-located small-molecule hormone receptorsinteracting with G proteins might also activate adenylatecyclase which results in the generation of yet anothersecondary messenger cAMP and in the activation of cAMP-dependent proteins such as PKA and of their substrates[243ndash247] By nongenomic mechanisms small-moleculehormones also regulate the activity of ion channels influenc-ing cross-membrane movement of Na+ H+ Clminus and of K+[245 248 249]

Small-molecule hormones also bind to the proteinspresent in the cytoplasm commonly such proteins are cyto-plasmic fractions of nuclear receptors Upon hormone bind-ing the receptor interacts with numerous proteins elementsof various signal transduction pathways which as describedabove might be also activated by hormones on a ldquohigherrdquolevel namely that of a cell membrane receptor For exam-ple hormone-activated TR ER and RAR bind to a p85120572subunit of phosphatidylinositol 3 kinase Activated kinaseincreases production of IP3 which in turn activates themitogen-activated protein kinase (MAPK) pathway [250ndash252] Hormone-activated AR PR and ER bind to SH3 or toSH2 subunit of c-SRC tyrosine kinase localized close to thecell membrane Such binding activates c-SRC which subse-quently activatesMAPK and RASRAFMEKERK pathwaysleading to the phosphorylation of various cytoplasmic andnuclear receptors [253ndash255]

32 Nuclear Hormone Receptor Binding to Calmodulin Ofnote is nuclear hormone receptorsrsquo binding to CaM beingan example of cross-talking of hormonal signaling with othersignal transduction pathways Such binding has been provedfor ER120572 (but not for ER120573) AR and orphan receptor ERR120574among others [85ndash87 256ndash258] It results in the increasedstability of the receptor due to CaM-dependent protectionfrom degradation [85ndash87] CaM facilitates dimerization ofER120572 in the absence of 17120573-estradiol [86] The binding pro-foundly affects receptor function CaM is required for normaltransactivation by ER120572 since its elimination or blockage byantagonists prevents 17120573-estradiol from inducing transcrip-tional activity of this receptor [256 257] Similarly CaMstimulates transcriptional activity of AR (since its antagonistW-7 blocks AR-dependent expression of prostate-specificantigen) and of ERR120574 [258 259]

33 Hormone Binding to Nonreceptor Proteins Small-mole-cule hormones could also bind to another nonreceptor typecytoplasmic proteins For example 112057225(OH)

2D3 dehy-

droepiandrosterone (DHEA) and dexamethasone bind toPKC120572 PKC120574 and PKC120576 isoforms of PKC which results in


Table 2 Selected human pathologies associated with hormone receptors

Receptor Pathology

TR Mutation-related generalized and pituitary resistance to thyroid hormone [1ndash4] mutations andor altered expression invarious cancers [5ndash9]

RAR Translocation in acute promyelocytic leukemia [10] reduced expression in cancers [11] altered signaling in neurological andpsychiatric diseases [12]

VDRMutation-related resistance to 112057225(OH)2D3hereditary vitamin D resistant rickets [13ndash15] polymorphisms in osteoporosis[16] mutations in alopecia [17] altered expression and polymorphisms in various cancers [18ndash20] altered function ininflammation [21] altered function in liver pathology [22]

PPARMutations in insulin resistance in nonobese [23] mutations in familial partial lipodystrophy [23ndash25] excessivephosphorylation in insulin resistance and obesity [26] mutations in cancers low expression in cancers with poor prognosis[27] alterations in atherosclerosis inflammation and osteoarthritis [28ndash30]

RXR Polymorphisms in colorectal cancer and in metabolic diseases [31ndash33]

ERMutations and altered expression in breast cancer [34ndash36] altered posttranslational modifications in breast cancer [36 37]overexpression in endometriosis [38] polymorphisms in ovulatory dysfunction [39] impaired function in metabolic diseases[40]

ARMutation-related androgen insensitivity syndrome [41ndash43] overexpression mutations CAG repeat extension excessivereceptor phosphorylation in prostate cancer [26 41 44ndash46] CAG repeat extension in spinal and bulbar muscular atrophy[45 47] mutations and the AR gene trinucleotide repeat variations in male infertility [48] mental disorders [41]

PR Lack of expression in breast cancer [35 36] decreased expression in endometriosis [49] altered expression in testis of infertilemen [50]

GR Mutation-related glucocorticoid resistance [51 52] polymorphisms in tissue-specific sensitivity to glucocorticoids andhypersensitivity to glucocorticoids [52] polymorphisms in depression [53]

MR Mutations in mineralocorticoid resistance syndrome (pseudohypoaldosteronism type 1) [54] polymorphisms in depression[53] mutation in severe hypertension [55]

enzyme activation In addition PKC120572 isoform is also directlyactivated by aldosterone and by 17120573-estradiol while PKC120575isoform is activated by 17120573-estradiol [260 261]

34 Small-Molecule Hormones Action in MitochondriaSmall-molecule hormones modulate the function of mito-chondria by a number of mechanisms One of them is basedon the action of their nuclear receptors as transcriptionfactors Each mitochondrion has multiple copies of its ownDNA (mtDNA) encoding 37 genes including genes for 13proteins involved in oxidative phosphorylation A shortenedisoform of TR (mtTR1205721 so-called p43) RXR120572 (mtRXR120572)and PPAR1205742 (mtPPAR1205742) as well as full-lengthGR ER120572 andER120573 receptors are present in mitochondria [109 262ndash265]where they form dimers such as mtRXR120572p43 mtPPAR1205742p43 GRGR and ERER or couple with other transcriptionfactors It has been shown that glucocorticoids T3 and 17120573-estradiol acting by their mitochondrial receptors bound tomitochondrial HREs activate the transcription of mtDNAleading to an increased activity of oxidative phosphorylation

Another mechanism of small-molecule hormones actionin mitochondria is based on their interactions with otherproteins For example diiodothyronine (T2) binds to the Vasubunit of cytochrome 119888 oxidase and activates this enzyme[266] Adenine nucleotide translocase (ANT) binds all-trans-retinoic acid [267]

In addition the shortest isoform of TR1205721 p28 is boundto the internal mitochondrial membrane [263] where mostlikely it stimulates the function of ANT and of uncouplingproteins (UCPs) [263 268] Orphan nuclear receptor Nur77

mediates apoptosis by interaction with Bcl-2 and by induc-tion of cytochrome 119888 release [269]

Small-molecule hormones acting in mitochondria regu-late Ca2+ wave activity in this organelle as shown in the caseof estrogens and T3 [270 271]

Finally hormonal receptors can directly bind to mito-chondrial membranes and modify membrane potential asshown for example for stress-activated GR [272]

35 Interaction of Hormonal Nuclear Receptors with RNA Ithas been shown that RAR120572 molecules present in the cyto-plasm can bind mRNA via the C-terminal F domain whichrecognizes a specific sequences in the target mRNA Sucha mechanism was described for mRNA encoding neuronalGluR1 protein a subunit of the glutaminergic receptor Thebinding of GluR1 mRNA by a hormone-free receptor resultsin the inhibition of translation The binding of all-trans-retinoic acid induces the change of receptor conformationand decreases its affinity for mRNA as a result the receptordissociates from mRNA [273]

36 Direct Interaction of Small-Molecule Hormones withMembranes A very rapid effects of androgens progesteroneglucocorticoids and other steroid hormones evident justa few seconds after hormone administration might be aresult of a nonspecific nongenomic mechanism of small-molecule hormones action based on their interactions withlipid bilayers Lipophilic steroid hormone molecules coulddirectly bind to membrane phospholipids and by doingso modulate their function This in turn influences the


function ofmembrane proteins such as the calciumpumpandother channel proteins leading to an immediate transportmodification of various ions Nonspecific binding of steroidhormones to a mitochondrial membrane might increaseproton leak [274 275]

4 Human Pathologies Associated withReceptor Abnormalities

Medical conditions associated with out-of-range level ofsmall-molecule hormones are known for decades relativelycommon and have been exhaustively described in numeroushandbooks and articles In contrastmuch less is known aboutdiseases initiated by abnormalities of the receptor They areuncommon with a wide range of signs and symptoms ofvariable severity (related to both the type and site of geneticerror within the receptor-encoding gene or related genes)that might mimic signs and symptoms of other diseases(eg resistance to thyroid hormone might be erroneouslydiagnosed as hyperthyroidism) Detailed description of thesediseases exceeds the scope of this paper however in Table 2the reader can find a comprehensive summary and referencesto the review and original articles regarding selected humanhormone-receptor-related pathologies

Hormone-receptor-related diseases constitute an impor-tant diagnostic challenge Among them a monogenic dis-eases arising due to mutation are the easiest to diagnoseprovided that a candidate gene is identified and its sequencingshowsmutation It is muchmore difficult though to evaluatethe influence of altered expression or function (eg due tothe abnormal posttranslationalmodifications) of the receptoron the phenotype especially ofmultifactorial diseases such asobesity insulin resistance atherosclerosis cardiovascular dis-ease cancer neurodegeneration and so forth the Diagnosticproblems are the reasonswhyhormone receptor dysfunctionscommonly remain undiagnosed and untreated Howeverthe importance of such dysfunctions in pathophysiology ofboth rare and common diseases fully justifies the effortsto elucidate the molecular mechanisms of action of thesereceptors Importantly identification of these mechanisms iscrucial for designing new targeted therapeutic strategies

5 Conclusion

Small-molecule hormones usually of quite simple chemicalstructure have an enormously wide range of biologicalfunctions The effects of their action are due to their inter-action with various receptors which by further interactionwith other proteins or with DNA activate various signaltransduction pathways or regulate the activity of numeroustarget genes Even though our knowledge regarding thesenongenomic and genomic mechanisms is already impressivea lot of information regarding first of all their interdepen-dence still awaits elucidation

References

[1] S Suzuki S Shigematsu H Inaba M Takei T Takedaand M Komatsu ldquoPituitary resistance to thyroid hormones

pathophysiology and therapeutic optionsrdquo Endocrine vol 40no 3 pp 366ndash371 2011

[2] A M Ferrara K Onigata O Ercan HWoodhead R E Weissand S Refetoff ldquoHomozygous thyroid hormone receptor b genemutations in resistance to thyroid hormone three new casesand review of the literaturerdquo Journal of Clinical Endocrinologyand Metabolism vol 97 no 4 pp 1328ndash1336 2012

[3] S Kannan and J D Safer ldquoFinding the right balance betweenresistance and sensitivity a review of the cardiacmanifestationsof the syndrome of resistance to thyroid hormone and theimplications for treatmentrdquo Endocrine Practice vol 18 no 2 pp252ndash255 2012

[4] A van Mullem R van Heerebeek D Chrysis et al ldquoClinicalphenotype and mutant TRa1rdquo The New England Journal ofMedicine vol 366 no 15 pp 1451ndash1453 2012

[5] O Turowska A Nauman M Pietrzak et al ldquoOverexpressionof E2F1 in clear cell renal cell carcinoma a potential impactof erroneous regulation by thyroid hormone nuclear receptorsrdquoThyroid vol 17 no 11 pp 1039ndash1048 2007

[6] C Lu and S Y Cheng ldquoExtranuclear signaling of mutatedthyroid hormone receptors in promoting metastatic spread inthyroid carcinogenesisrdquo Steroids vol 76 no 9 pp 885ndash891 2011

[7] M D Rosen and M L Privalsky ldquoThyroid hormone receptormutations in cancer and resistance to thyroid hormone per-spective and prognosisrdquo Journal of Thyroid Research Article ID361304 2011

[8] C Lu A Mishra Y J Zhu P Meltzer and S Y Cheng ldquoGlobalexpression profiling reveals gain-of-function oncogenic activityof a mutated thyroid hormone receptor in thyroid carcinogene-sisrdquo American Journal of Cancer Research vol 1 no 2 pp 168ndash191 2011

[9] M D Rosen I H Chan and M L Privalsky ldquoMutant thyroidhormone receptors (TRs) isolated from distinct cancer typesdisplay distinct target gene specificities a unique regulatoryrepertoire associated with two renal clear cell carcinomasrdquoMolecular Endocrinology vol 25 no 8 pp 1311ndash1325 2011

[10] Z Chen Z Y Wang and S J Chen ldquoAcute promyelocyticleukemia cellular and molecular basis of differentiation andapoptosisrdquo Pharmacology and Therapeutics vol 76 no 1ndash3 pp141ndash149 1997

[11] J Olasz A Juhasz E Remenar et al ldquoRAR1205732 suppression inhead and neck squamous cell carcinoma correlates with sitehistology and agerdquo Oncology Reports vol 18 no 1 pp 105ndash1122007

[12] S van Neerven E Kampmann and J Mey ldquoRARRXR andPPARRXR signaling in neurological and psychiatric diseasesrdquoProgress in Neurobiology vol 85 no 4 pp 433ndash451 2008

[13] T M Nguyen P Adiceam M L Kottler et al ldquoTryptophanmissensemutation in the ligand-binding domain of the vitaminD receptor causes severe resistance to 125-dihydroxyvitaminDrdquo Journal of Bone andMineral Research vol 17 no 9 pp 1728ndash1737 2002

[14] J M Aljubeh J Wang S S Al-Remeithi P J Malloy and DFeldman ldquoReport of two unrelated patients with hereditaryvitamin D resistant rickets due to the same novel mutation inthe vitamin D receptorrdquo Journal of Pediatric Endocrinology andMetabolism vol 24 no 9-10 pp 793ndash799 2011

[15] P J Malloy Y Zhou J Wang O Hiort and D FeldmanldquoHereditary vitamin D-resistant rickets (HVDRR) owing to aheterozygous mutation in the vitamin D receptorrdquo Journal ofBone and Mineral Research vol 26 no 11 pp 2710ndash2718 2011


[16] F Massart G Marcucci and M L Brandt ldquoPharmacogeneticsof bone treatments the VDR and ER120572 gene storyrdquo Pharmacoge-nomics vol 9 no 6 pp 733ndash746 2008

[17] P J Malloy and D Feldman ldquoThe role of vitamin D receptormutations in the development of alopeciardquo Molecular andCellular Endocrinology vol 347 no 1-2 pp 90ndash96 2011

[18] K Kostner N Denzer C S L Muller R Klein W Tilgenand J Reichrath ldquoThe relevance of Vitamin D Receptor (VDR)gene polymorphisms for cancer a review of the literaturerdquoAnticancer Research vol 29 no 9 pp 3511ndash3536 2009

[19] S Field and J A Newton-Bishop ldquoMelanoma and vitamin DrdquoMolecular Oncology vol 5 no 2 pp 197ndash214 2011

[20] J Welsh ldquoCellular and molecular effects of vitamin D on car-cinogenesisrdquo Archives of Biochemistry and Biophysics vol 523no 1 pp 107ndash114 2012

[21] SWu and J Sun ldquoVitaminD vitaminD receptor andmacroau-tophagy in inflammation and infectionrdquo Discovery Medicinevol 11 no 59 pp 325ndash335 2011

[22] S Zuniga D Firrincieli C Housset andN Chignard ldquoVitaminD and the vitamin D receptor in liver pathophysiologyrdquo Clinicsand Research in Hepatology and Gastroenterology vol 35 no 4pp 295ndash302 2011

[23] M E Visser E Kropman M E Kranendonk et al ldquoCharac-terisation of non-obese diabetic patients with marked insulinresistance identifies a novel familial partial lipodystrophy-associated PPAR120574 mutation (Y151C)rdquo Diabetologia vol 54 no7 pp 1639ndash1644 2011

[24] E H Jeninga and E Kalkhoven ldquoCentral players in inheritedlipodystrophiesrdquo Trends in Endocrinology and Metabolism vol21 no 10 pp 581ndash588 2010

[25] C Vigouroux M Caron-Debarle C Le Dour J Magre andJ Capeau ldquoMolecular mechanisms of human lipodystrophiesfrom adipocyte lipid droplet to oxidative stress and lipotoxicityrdquoInternational Journal of Biochemistry and Cell Biology vol 43no 6 pp 862ndash876 2011

[26] M Anbalagan B Huderson L Murphy and B G RowanldquoPost-translational modifications of nuclear receptors andhuman diseaserdquoNuclear Receptor Signaling vol 10 article e0012012

[27] G T Robbins and D Nie ldquoPPARg bioactive lipids and cancerprogressionrdquo Frontiers in Bioscience vol 17 pp 1816ndash1834 2012

[28] N Wang R Yin Y Liu G Mao and F Xi ldquoRole of peroxisomeproliferator-activated receptor-120574 in atherosclerosis an updaterdquoCirculation Journal vol 75 no 3 pp 528ndash535 2011

[29] H Martin ldquoRole of PPAR-gamma in inflammation Prospectsfor therapeutic intervention by food componentsrdquo MutationResearch vol 690 no 1-2 pp 57ndash63 2010

[30] H Fahmi J Martel-Pelletier J P Pelletier andM Kapoor ldquoPer-oxisome proliferator-activated receptor gamma in osteoarthri-tisrdquoModern Rheumatology vol 21 no 1 pp 1ndash9 2011

[31] E T Jacobs M E Martınez P T Campbell et al ldquoGeneticvariation in the retinoid X receptor and calcium-sensing recep-tor and risk of colorectal cancer in the Colon Cancer FamilyRegistryrdquo Carcinogenesis vol 31 no 8 pp 1412ndash1416 2010

[32] C H Hsieh D Pei Y J Hung and F C Hsiao ldquoAssociationbetween retinoid-X receptor g genetic polymorphisms anddiabetic retinopathyrdquo Genetics and Molecular Research vol 10no 4 pp 3545ndash3551 2011

[33] H Shi X Yu Q Li et al ldquoAssociation between PPAR120574 andRXR120572 gene polymorphism and metabolic syndrome risk acase-control study of a Chinese Han populationrdquo Archives ofMedical Research vol 43 no 3 pp 233ndash242 2012

[34] I Barone L Brusco and S A W Fuqua ldquoEstrogen receptormutations and changes in downstream gene expression andsignalingrdquo Clinical Cancer Research vol 16 no 10 pp 2702ndash2708 2010

[35] M D Valentin S D da Silva M Privat M Alaoui-Jamali andY J Bignon ldquoMolecular insights on basal-like breast cancerrdquoBreast Cancer Research and Treatment vol 134 no 1 pp 21ndash302012

[36] W Eiermann J Bergh F Cardoso et al ldquoTriple negative breastcancer proposals for a pragmatic definition and implicationsfor patient management and trial designrdquo Breast vol 21 no 1pp 20ndash26 2012

[37] M Le Romancer C Poulard P Cohen S Sentis J M Renoirand L Corbo ldquoCracking the estrogen receptorrsquos posttransla-tional code in breast tumorsrdquo Endocrine Reviews vol 32 no 5pp 597ndash622 2011

[38] S E Bulun D Monsavais M E Pavone et al ldquoRole ofestrogen receptor120573 in endometriosisrdquo Seminars in ReproductiveMedicine vol 30 no 1 pp 39ndash45 2012

[39] A E Drummond and P J Fuller ldquoOvarian actions of estrogenreceptor b an updaterdquo Seminars in Reproductive Medicine vol30 no 1 pp 32ndash38 2012

[40] M H Faulds C Zhao K Dahlman-Wright and J A Gustafs-son ldquoThe diversity of sex steroid action regulation of metabo-lism by estrogen signalingrdquo Journal of Endocrinology vol 212no 1 pp 3ndash12 2012

[41] S Rajender L Singh and K Thangaraj ldquoPhenotypic hetero-geneity of mutations in androgen receptor generdquo Asian Journalof Andrology vol 9 no 2 pp 147ndash179 2007

[42] A Galani S Kitsiou-Tzeli C Sofokleous E Kanavakis andA Kalpini-Mavrou ldquoAndrogen insensitivity syndrome clinicalfeatures andmolecular defectsrdquoHormones vol 7 no 3 pp 217ndash229 2008

[43] I A Hughes J D Davies T I Bunch V Pasterski K Mas-troyannopoulou and J MacDougall ldquoAndrogen insensitivitysyndromerdquoThe Lancet vol 380 no 9851 pp 1419ndash1428 2012

[44] P Saraon K Jarvi and E P Diamandis ldquoMolecular alterationsduring progression of prostate cancer to androgen indepen-dencerdquo Clinical Chemistry vol 57 no 10 pp 1366ndash1375 2011

[45] R Kumar H Atamna M N Zakharov S Bhasin S H Khanand R Jasuja ldquoRole of the androgen receptor CAG repeat poly-morphism in prostate cancer and spinal and bulbar muscularatrophyrdquo Life Sciences vol 88 no 13-14 pp 565ndash571 2011

[46] J P Bergerat and J Ceraline ldquoPleiotropic functional propertiesof androgen receptor mutants in prostate cancerrdquo HumanMutation vol 30 no 2 pp 145ndash157 2009

[47] M Katsuno H Banno K Suzuki H Adachi F Tanaka andG Sobue ldquoClinical features and molecular mechanisms ofspinal and bulbar muscular atrophy (SBMA)rdquo Advances inExperimental Medicine and Biology vol 685 pp 64ndash74 2010

[48] B Gottlieb R Lombroso L K Beitel and M A TrifiroldquoMolecular pathology of the androgen receptor in male (in)fertilityrdquoReproductive BioMedicineOnline vol 10 no 1 pp 42ndash48 2005

[49] S E Bulun Y H Cheng M E Pavone et al ldquoEstrogenreceptor-120573 estrogen receptor-120572 and progesterone resistance inendometriosisrdquo Seminars in Reproductive Medicine vol 28 no1 pp 36ndash43 2010

[50] S Abid J Gokral A Maitra et al ldquoAltered expression ofprogesterone receptors in testis of infertile menrdquo ReproductiveBioMedicine Online vol 17 no 2 pp 175ndash184 2008


[51] E F C van Rossum and S W J Lamberts ldquoGlucocorticoidresistance syndrome a diagnostic and therapeutic approachrdquoBest Practice and Research vol 20 no 4 pp 611ndash626 2006

[52] N C Nicolaides Z Galata T Kino G P Chrousos and ECharmandari ldquoThe human glucocorticoid receptor molecularbasis of biologic functionrdquo Steroids vol 75 no 1 pp 1ndash12 2010

[53] R H DeRijk and E R de Kloet ldquoCorticosteroid receptorpolymorphisms determinants of vulnerability and resiliencerdquoEuropean Journal of Pharmacology vol 583 no 2-3 pp 303ndash311 2008

[54] T Kino and G P Chrousos ldquoGlucocorticoid and mineralocor-ticoid receptors and associated diseasesrdquo Essays in Biochemistryvol 40 pp 137ndash155 2004

[55] M E Rafestin-Oblin A Souque B Bocchi G Pinon J Fagartand A Vandewalle ldquoThe severe form of hypertension caused bythe activating S810Lmutation in themineralocorticoid receptoris cortisone relatedrdquo Endocrinology vol 144 no 2 pp 528ndash5332003

[56] Nuclear Receptors Nomenclature Committee ldquoA unifiednomenclature system for the nuclear receptor superfamilyrdquoCell vol 97 no 2 pp 161ndash163 1999

[57] H Escriva S Bertrand and V Laudet ldquoThe evolution of thenuclear receptor superfamilyrdquo Essays in Biochemistry vol 40pp 11ndash26 2004

[58] P Germain B Staels C Dacquet M Spedding and V LaudetldquoOverview of nomenclature of nuclear receptorsrdquo Pharmacolog-ical Reviews vol 58 no 4 pp 685ndash704 2006

[59] C Rochette-Egly M P Gaub Y Lutz S Ali I Scheuer andP Chambon ldquoRetinoic acid receptor-120573 immunodetection andphosphorylation on tyrosine residuesrdquo Molecular Endocrinol-ogy vol 6 no 12 pp 2197ndash2209 1992

[60] C E Juge-Aubry E Hammar C Siegrist-Kaiser et al ldquoReg-ulation of the transcriptional activity of the peroxisomeproliferator-activated receptor by phosphorylation of a ligand-independent trans-activating domainrdquo Journal of BiologicalChemistry vol 274 no 15 pp 10505ndash10510 1999

[61] M Nordzell P Aarnisalo G Benoit D S Castro and TPerlmann ldquoDefining an N-terminal activation domain of theorphan nuclear receptor Nurr1rdquo Biochemical and BiophysicalResearch Communications vol 313 no 1 pp 205ndash211 2004

[62] P Rajbhandari G Finn N M Solodin et al ldquoRegulation ofestrogen receptor N-terminus conformation and function bypeptidyl prolyl isomerase Pin1rdquoMolecular and Cellular Biologyvol 32 no 2 pp 445ndash457 2012

[63] B F Luisi W X Xu Z Otwinowski L P Freedman K RYamamoto and P B Sigler ldquoCrystallographic analysis of theinteraction of the glucocorticoid receptor with DNArdquo Naturevol 352 no 6335 pp 497ndash505 1991

[64] J W R Schwabe L Chapman J T Finch and D RhodesldquoThe crystal structure of the estrogen receptor DNA-bindingdomain bound to DNA how receptors discriminate betweentheir response elementsrdquo Cell vol 75 no 3 pp 567ndash578 1993

[65] T Miyamoto T Kakizawa K Ichikawa et al ldquoThe role of hingedomain in heterodimerization and specific DNA recognition bynuclear receptorsrdquo Molecular and Cellular Endocrinology vol181 no 1-2 pp 229ndash238 2001

[66] J M Wurtz W Bourguet J P Renaud et al ldquoA canonicalstructure for the ligand-binding domain of nuclear receptorsrdquoNature Structural Biology vol 3 no 1 pp 87ndash94 1996

[67] J Uppenberg C Svensson M Jaki G Bertilsson L Jendebergand A Berkenstam ldquoCrystal structure of the ligand binding

domain of the human nuclear receptor PPAR120574rdquo Journal ofBiological Chemistry vol 273 no 47 pp 31108ndash31112 1998

[68] W Bourguet M Ruff P Chambon H Gronemeyer and DMoras ldquoCrystal structure of the ligand-binding domain of thehuman nuclear receptor RXR-120572rdquo Nature vol 375 no 6530 pp377ndash382 1995

[69] S Nayeri J P Kahlen andG Carlberg ldquoThe high affinity ligandbinding conformation of the nuclear 125-dihydroxyvitaminD3receptor is functionally linked to the transactivation domain 2(AF-2)rdquo Nucleic Acids Research vol 24 no 22 pp 4513ndash45181996

[70] A M Brzozowski A C W Pike Z Dauter et al ldquoMolecularbasis of agonism and antagonism in the oestrogen receptorrdquoNature vol 389 no 6652 pp 753ndash758 1997

[71] R L Wagner J W Apriletti M E McGrath B L West J DBaxter and R J Fletterick ldquoA structural role for hormone inthe thyroid hormone receptorrdquo Nature vol 378 no 6558 pp690ndash697 1995

[72] M D M Huq S G Ha and L N Wei ldquoModulation of retinoicacid receptor alpha activity by lysine methylation in the DNAbinding domainrdquo Journal of Proteome Research vol 7 no 10pp 4538ndash4545 2008

[73] P La Rosa V Pesiri G Leclercq M Marino and F AcconcialdquoPalmitoylation regulates 17120573-estradiol-induced estrogenreceptor 120572 degradation and transcriptional activityrdquo MolecularEndocrinology vol 26 no 5 pp 762ndash774 2012

[74] H A Abdel-Hafiz and K B Horwitz ldquoControl of proges-terone receptor ranscriptional synergy by SUMOylation anddeSUMOylationrdquo BMCMolecular Biology vol 22 no 13 article10 2012

[75] S Chen S Gulla C Cai and S P Balk ldquoAndrogen receptorserine 81 phosphorylation mediates chromatin binding andtranscriptional activationrdquo Journal of Biological Chemistry vol287 no 11 pp 8571ndash8583 2012


[77] A D Wallace and J A Cidlowski ldquoProteasome-mediated glu-cocorticoid receptor degradation restricts transcriptional sig-naling by glucocorticoidsrdquo Journal of Biological Chemistry vol276 no 46 pp 42714ndash42721 2001

[78] A Ciechanover A Orian and A L Schwartz ldquoUbiquitin-mediated proteolysis biological regulation via destructionrdquoBioessays vol 22 no 5 pp 442ndash451 2000

[79] S Sengupta and B Wasylyk ldquoLigand-dependent interaction ofthe glucocorticoid receptor with p53 enhances their degrada-tion byHdm2rdquoGenes andDevelopment vol 15 no 18 pp 2367ndash2380 2001

[80] X Wang and D B DeFranco ldquoAlternative effects of the ubiq-uitin-proteasome pathway on glucocorticoid receptor down-regulation and transactivation are mediated by CHIP an E3ligaserdquo Molecular Endocrinology vol 19 no 6 pp 1474ndash14822005

[81] D M Lonard Z Nawaz C L Smith and B W OrsquoMalleyldquoThe 26S proteasome is required for estrogen receptor-120572 andcoactivator turnover and for efficient estrogen receptor-120572 trans-activationrdquoMolecular Cell vol 5 no 6 pp 939ndash948 2000

[82] B J Deroo C Rentsch S Sampath J Young D B DeFrancoand T K Archer ldquoProteasomal inhibition enhances gluco-corticoid receptor transactivation and alters its subnuclear


traffickingrdquo Molecular and Cellular Biology vol 22 no 12 pp4113ndash4123 2002

[83] W B Pratt M D Galigniana Y Morishima and P J MMurphy ldquoRole of molecular chaperones in steroid receptoractionrdquo Essays in Biochemistry vol 40 pp 41ndash58 2004

[84] W B Pratt Y Morishima M Murphy and M Harrell ldquoChap-eroning of glucocorticoid receptorsrdquoHandbook of experimentalpharmacology no 172 pp 111ndash138 2006

[85] L Li Z Li P M Howley and D B Sacks ldquoE6AP and calmod-ulin reciprocally regulate estrogen receptor stabilityrdquo Journal ofBiological Chemistry vol 281 no 4 pp 1978ndash1985 2006

[86] Y Zhang Z Li D B Sacks and J B Ames ldquoStructural basis forCa2+-induced activation and dimerization of estrogen receptora by calmodulinrdquo Journal of Biological Chemistry vol 287 no12 pp 9336ndash9344 2012

[87] A Sivanandam S Murthy K Chinnakannu et al ldquoCalmodulinprotects androgen receptor from calpain-mediated breakdownin prostate cancer cellsrdquo Journal of Cellular Physiology vol 226no 7 pp 1889ndash1896 2011


[89] K Chatterjee J K Lee A Rentoumis and J L Jameson ldquoNeg-ative regulation of the thyroid-stimulating hormone 120572 gene bythyroid hormone receptor interaction adjacent to the TATAboxrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 86 no 23 pp 9114ndash9118 1989

[90] S Seoane M Alonso C Segura and R Perez-FernandezldquoLocalization of a negative vitamin D response sequence inthe human growth hormone generdquo Biochemical and BiophysicalResearch Communications vol 292 no 1 pp 250ndash255 2002

[91] A Weisz L Coppola and F Bresciani ldquoSpecific binding ofestrogen receptor to sites upstream and within the transcribedregion of the chicken ovalbumin generdquo Biochemical and Bio-physical Research Communications vol 139 no 2 pp 396ndash4021986

[92] J La Baer and K R Yamamoto ldquoAnalysis of the DNA-bindingaffinity sequence specificity and context dependence of theglucocorticoid receptor zinc finger regionrdquo Journal of MolecularBiology vol 239 no 5 pp 664ndash688 1994

[93] F Claessens and D T Gewirth ldquoDNA recognition by nuclearreceptorsrdquo Essays in Biochemistry vol 40 pp 59ndash72 2004

[94] S Y Tsai J Carlstedt-Duke N L Weigel et al ldquoMolecularinteractions of steroid hormone receptor with its enhancerelement evidence for receptor dimer formationrdquo Cell vol 55no 2 pp 361ndash369 1988

[95] C M Klinge D L Bodenner D Desai R M Niles and AM Traish ldquoBinding of type II nuclear receptors and estrogenreceptor to full and half-site estrogen response elements inVitrordquoNucleic Acids Research vol 25 no 10 pp 1903ndash1912 1997

[96] R C J Ribeiro W Feng R L Wagner et al ldquoDefinition of thesurface in the thyroid hormone receptor ligand binding domainfor association as homodimers and heterodimers with retinoidX receptorrdquo Journal of Biological Chemistry vol 276 no 18 pp14987ndash14995 2001

[97] Y Brelivet S Kammerer N Rochel O Poch and D MorasldquoSignature of the oligomeric behaviour of nuclear receptors atthe sequence and structural levelrdquo EMBO Reports vol 5 no 4pp 423ndash429 2004

[98] S Lee and M L Privalsky ldquoHeterodimers of retinoic acidreceptors and thyroid hormone receptors display unique com-binatorial regulatory propertiesrdquoMolecular Endocrinology vol19 no 4 pp 863ndash878 2005

[99] E Powell and W Xu ldquoIntermolecular interactions identifyligand-selective activity of estrogen receptor 120572120573 dimersrdquo Pro-ceedings of the National Academy of Sciences of the United Statesof America vol 105 no 48 pp 19012ndash19017 2008

[100] T E Wilson T J Fahrner and J Milbrandt ldquoThe orphanreceptorsNGFI-B and steroidogenic factor 1 establishmonomerbinding as a third paradigm of nuclear receptor-DNA interac-tionrdquo Molecular and Cellular Biology vol 13 no 9 pp 5794ndash5804 1993

[101] D J Mangelsdorf C Thummel M Beato et al ldquoThe nuclearreceptor super-family the second decaderdquo Cell vol 83 no 6pp 835ndash839 1995

[102] M Danielsen L Hinck and G M Ringold ldquoTwo amino acidswithin the knuckle of the first zinc finger specify DNA responseelement activation by the glucocorticoid receptorrdquo Cell vol 57no 7 pp 1131ndash1138 1989

[103] G Verrijdt E Schoenmakers A Haelens et al ldquoChange ofspecificity mutations in androgen-selective enhancers Evi-dence for a role of differential DNA binding by the androgenreceptorrdquo Journal of Biological Chemistry vol 275 no 16 pp12298ndash12305 2000

[104] P L Shaffer A Jivan D E Dollins F Claessens and DT Gewirth ldquoStructural basis of androgen receptor bindingto selective androgen response elementsrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 101 no 14 pp 4758ndash4763 2004

[105] S Denayer C Helsen L Thorrez A Haelens and F ClaessensldquoThe rules of DNA recognition by the androgen receptorrdquoMolecular Endocrinology vol 24 no 5 pp 898ndash913 2010

[106] F Aslam V Shalhoub A J VanWijnen et al ldquoContributions ofdistal and proximal promoter elements to glucocorticoid regu-lation of osteocalcin gene transcriptionrdquoMolecular Endocrinol-ogy vol 9 no 6 pp 679ndash690 1995

[107] X M Ou J M Storring N Kushwaha and P R AlbertldquoHeterodimerization of mineralocorticoid and glucocorticoidreceptors at a novel negative response element of the 5-HT1Areceptor generdquo Journal of Biological Chemistry vol 276 no 17pp 14299ndash14307 2001

[108] M M V Ruiz T H Bugge P Hirschmann and H GStunnenberg ldquoFunctional characterization of a natural retinoicacid responsive elementrdquo EMBO Journal vol 10 no 12 pp3829ndash3838 1991

[109] F Casas L Daury S Grandemange et al ldquoEndocrine regulationof mitochondrial activity involvement of truncated RXR120572 andc-Erb a1205721 proteinsrdquo FASEB Journal vol 17 no 3 pp 426ndash4362003

[110] G R Williams A M Zavacki J W Harney and G A BrentldquoThyroid hormone receptor binds with unique properties toresponse elements that contain hexamer domains in an invertedpalindrome arrangementrdquo Endocrinology vol 134 no 4 pp1888ndash1896 1994

[111] M Ikeda M Rhee and W W Chin ldquoThyroid hormone recep-tor monomer homodimer and heterodimer (with retinoid-X receptor) contact different nucleotide sequences in thyroidhormone response elementsrdquo Endocrinology vol 135 no 4 pp1628ndash1638 1994


[112] M A Hirst L Hinck M Danielsen and G M RingoldldquoDiscrimination of DNA response elements for thyroid hor-mone and estrogen is dependent on dimerization of receptorDNA binding domainsrdquo Proceedings of the National Academy ofSciences of the United States of America vol 89 no 12 pp 5527ndash5531 1992

[113] T L Towers B F Luisi A Asianov and L P Freedman ldquoDNAtarget selectivity by the vitamin D3 receptor mechanism ofdimer binding to an asymmetric repeat elementrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 90 no 13 pp 6310ndash6314 1993

[114] T Miyamoto S Suzuki and L J DeGroot ldquoHigh affinity andspecificity of dimeric binding of thyroid hormone receptorsto DNA and their ligand-dependent dissociationrdquo MolecularEndocrinology vol 7 no 2 pp 224ndash231 1993

[115] T Miyamoto S Suzuki and L J DeGroot ldquoDifferential bind-ing and activation of thyroid hormone response elements byTR(1205721) and RXR(120572)-trap heterodimersrdquoMolecular and CellularEndocrinology vol 102 no 1-2 pp 111ndash117 1994

[116] C Carlberg I Bendik A Wyss et al ldquoTwo nuclear signallingpathways for vitamin DrdquoNature vol 361 no 6413 pp 657ndash6601993

[117] Z H Yan A Medvedev T Hirose H Gotoh and A M JettenldquoCharacterization of the response element and DNA bindingproperties of the nuclear orphan receptor germ cell nuclear fac-torretinoid receptor- related testis-associated receptorrdquo Journalof Biological Chemistry vol 272 no 16 pp 10565ndash10572 1997

[118] R Schule K Umesono D J Mangelsdorf J Bolado J WPike and R M Evans ldquoJun-Fos and receptors for vitamins Aand D recognize a common response element in the humanosteocalcin generdquo Cell vol 61 no 3 pp 497ndash504 1990

[119] M A Lazar and T J Berrodin ldquoThyroid hormone recep-tors form distinct nuclear protein-dependent and independentcomplexes with a thyroid hormone response elementrdquoMolecu-lar Endocrinology vol 4 no 11 pp 1627ndash1635 1990

[120] S Faisst and S Meyer ldquoCompilation of vertebrate-encodedtranscription factorsrdquo Nucleic Acids Research vol 20 no 1 pp3ndash26 1992

[121] J Kirfel M Kelter L M Cancela P A Price and R SchuleldquoIdentification of a novel negative retinoic acid responsiveelement in the promoter of the humanmatrix Gla protein generdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 94 no 6 pp 2227ndash2232 1997

[122] D W Eubank E Duplus S C Williams C Forest and EG Beale ldquoPeroxisome proliferator-activated receptor 120574 andchicken ovalbumin upstream promoter transcription factorII negatively regulate the phosphoenolpyruvate carboxykinasepromoter via a common elementrdquo Journal of Biological Chem-istry vol 276 no 32 pp 30561ndash30569 2001

[123] M S Kim R Fujiki A Murayama et al ldquo112057325(OH)2D3-

induced transrepression by vitamin D receptor through E-box-type elements in the human parathyroid hormone genepromoterrdquoMolecular Endocrinology vol 21 no 2 pp 334ndash3422007

[124] C J Guigon D W Kim X Zhu L Zhao and S Y ChengldquoTumor suppressor action of liganded thyroid hormone recep-tor 120573 by direct repression of 120573-catenin gene expressionrdquoEndocrinology vol 151 no 11 pp 5528ndash5536 2010

[125] H P Harding and M A Lazar ldquoThe orphan receptor Rev-ErbA120572 activates transcription via a novel response elementrdquoMolecular and Cellular Biology vol 13 no 5 pp 3113ndash3121 1993

[126] V Giguere M Tini G Flock E Ong R M Evans andG Otulakowski ldquoIsoform-specific amino-terminal domainsdictate DNA-binding properties of ROR120572 a novel family oforphan hormone nuclear receptorsrdquo Genes and Developmentvol 8 no 5 pp 538ndash553 1994

[127] W B Pratt and D O Toft ldquoSteroid receptor interactions withheat shock protein and immunophilin chaperonesrdquo EndocrineReviews vol 18 no 3 pp 306ndash360 1997

[128] K Graumann and A Jungbauer ldquoQuantitative assessment ofcomplex formation of nuclear-receptor accessory proteinsrdquoBiochemical Journal vol 345 no 3 pp 627ndash636 2000

[129] T Rajapandi L E Greene and E Eisenberg ldquoThe molecularchaperones Hsp90 and Hsc70 are both necessary and sufficientto activate hormone binding by glucocorticoid receptorrdquo Jour-nal of Biological Chemistry vol 275 no 29 pp 22597ndash226042000

[130] N S Cintron and D Toft ldquoDefining the requirements forHsp40 and Hsp70 in the Hsp90 chaperone pathwayrdquo Journal ofBiological Chemistry vol 281 no 36 pp 26235ndash26244 2006

[131] J P Schulke G M Wochnik I Lang-Rollin et al ldquoDifferentialimpact of tetratricopeptide repeat proteins on the steroidhormone receptorsrdquo PloS one vol 5 no 7 article e11717 2010

[132] M Nishi andM Kawata ldquoDynamics of glucocorticoid receptorand mineralocorticoid receptor implications from live cellimaging studiesrdquoNeuroendocrinology vol 85 no 3 pp 186ndash1922007

[133] M Kawata M Nishi K Matsuda et al ldquoSteroid receptor sig-nalling in the brainmdashlessons learned frommolecular imagingrdquoJournal of Neuroendocrinology vol 20 no 6 pp 673ndash676 2008

[134] C Elbi D A Walker G Romero et al ldquoMolecular chaperonesfunction as steroid receptor nuclear mobility factorsrdquo Proceed-ings of the National Academy of Sciences of the United States ofAmerica vol 101 no 9 pp 2876ndash2881 2004

[135] T E Spencer G Jenster M M Burcin et al ldquoSteroid receptorcoactivator-1 is a histone acetyltransferaserdquoNature vol 389 no6647 pp 194ndash198 1997

[136] Z Liu J Wong S Y Tsai M J Tsai and B W OrsquoMalleyldquoSequential recruitment of steroid receptor coactivator-1 (SRC-1) and p300 enhances progesterone receptor-dependent initia-tion and reinitiation of transcription from chromatinrdquo Proceed-ings of the National Academy of Sciences of the United States ofAmerica vol 98 no 22 pp 12426ndash12431 2001

[137] M Y Kim S J Hsiao and W L Kraus ldquoA role for coactivatorsand histone acetylation in estrogen receptor 120572-mediated tran-scription initiationrdquo EMBO Journal vol 20 no 21 pp 6084ndash6094 2001

[138] B Belandia R L Orford H C Hurst and M G ParkerldquoTargeting of SWISNF chromatin remodelling complexes toestrogen-responsive genesrdquo EMBO Journal vol 21 no 15 pp4094ndash4103 2002

[139] Z Kang O A Janne and J J Palvimo ldquoCoregulator recruit-ment and histonemodifications in transcriptional regulation bythe androgen receptorrdquoMolecular Endocrinology vol 18 no 11pp 2633ndash2648 2004

[140] D J van de Wijngaart H J Dubbink M E van RoyenJ Trapman and G Jenster ldquoAndrogen receptor coregulatorsrecruitment via the coactivator binding grooverdquoMolecular andCellular Endocrinology vol 352 no 1-2 pp 57ndash69 2012

[141] D Pearce W Matsui J N Miner and K R YamamotoldquoGlucocorticoid receptor transcriptional activity determined byspacing of receptor and nonreceptor DNA sitesrdquo Journal ofBiological Chemistry vol 273 no 46 pp 30081ndash30085 1998


[142] P J Kushner D A Agard G L Greene et al ldquoEstrogenreceptor pathways to AP-1rdquo Journal of Steroid Biochemistry andMolecular Biology vol 74 no 5 pp 311ndash317 2000

[143] H Takai Y Nakayama D S Kim et al ldquoAndrogen recep-tor stimulates bone sialoprotein (BSP) gene transcription viacAMP response element and activator protein 1glucocorticoidresponse elementsrdquo Journal of Cellular Biochemistry vol 102 no1 pp 240ndash251 2007

[144] H Konig H Ponta H J Rahmsdorf and P Herrlich ldquoInterfer-ence between pathway-specific transcription factors glucocor-ticoids antagonize phorbol ester-induced AP-1 activity withoutaltering AP-1 site occupation in vivordquo EMBO Journal vol 11 no6 pp 2241ndash2246 1992

[145] N Gionet D Jansson S Mader and M A C Pratt ldquoNF-120581Band estrogen receptor 120572 interactions differential function inestrogen receptor-negative and -positive hormone-independ-ent breast cancer cellsrdquo Journal of Cellular Biochemistry vol 107no 3 pp 448ndash459 2009

[146] N A Rao M T McCalman P Moulos et al ldquoCoactivation ofGR and NFKB alters the repertoire of their binding sites andtarget genesrdquo Genome Research vol 21 no 9 pp 1404ndash14162011

[147] J D Chen and R M Evans ldquoA transcriptional co-repressor thatinteracts with nuclear hormone receptorsrdquo Nature vol 377 no6548 pp 454ndash457 1995

[148] A J Horlein AMNaar T Heinzel et al ldquoLigand-independentrepression by the thyroid hormone receptor mediated by anuclear receptor co-repressorrdquo Nature vol 377 no 6548 pp397ndash404 1995

[149] V Cavailles S Dauvois F LrsquoHorset et al ldquoNuclear factor RIP140modulates transcriptional activation by the estrogen receptorrdquoEMBO Journal vol 14 no 15 pp 3741ndash3751 1995

[150] I Fernandes Y Bastien T Wai et al ldquoLigand-dependentnuclear receptor corepressor LCoR functions by histonedeacetylase-dependent and -independent mechanismsrdquoMolec-ular Cell vol 11 no 1 pp 139ndash150 2003

[151] P Augereau E Badia S Carascossa et al ldquoThe nuclear receptortranscriptional coregulator RIP140rdquoNuclear Receptor Signalingvol 4 article e024 2006

[152] N Subramaniam W Cairns and S Okret ldquoGlucocorticoidsrepress transcription from a negative glucocorticoid responseelement recognized by two homeodomain-containing proteinsPbx and Oct-1rdquo Journal of Biological Chemistry vol 273 no 36pp 23567ndash23574 1998

[153] M AWilson and S A Chrysogelos ldquoIdentification and charac-terization of a negative regulatory element within the epidermalgrowth factor receptor gene first intron in hormone-dependentbreast cancer cellsrdquo Journal of Cellular Biochemistry vol 85 no3 pp 601ndash614 2002

[154] M V Govindan ldquoRecruitment of cAMP-response element-binding protein and histone deacetylase has opposite effects onglucocorticoid receptor gene transcriptionrdquo Journal of Biologi-cal Chemistry vol 285 no 7 pp 4489ndash4510 2010

[155] K Prufer and J Barsony ldquoRetinoid X Receptor dominatesthe nuclear import and export of the unliganded vitamin DreceptorrdquoMolecular Endocrinology vol 16 no 8 pp 1738ndash17512002

[156] X Cao W Liu F Lin et al ldquoRetinoid X receptor regulatesNur77TR3-dependent apoptosis by modulating its nuclearexport and mitochondrial targetingrdquo Molecular and CellularBiology vol 24 no 22 pp 9705ndash9725 2004

[157] V C Yu C Delsert B Andersen et al ldquoRXR120573 a coregulatorthat enhances binding of retinoic acid thyroid hormone andvitamin D receptors to their cognate response elementsrdquo Cellvol 67 no 6 pp 1251ndash1266 1991

[158] M Puzianowska-Kuznicka S Damjanovski and Y B ShildquoBoth thyroid hormone and 9-cis retinoic acid receptors arerequired to efficiently mediate the effects of thyroid hormoneon embryonic development and specific gene regulation inXenopus laevisrdquo Molecular and Cellular Biology vol 17 no 8pp 4738ndash4749 1997

[159] L Laflamme G Hamann N Messier S Maltais and M FLanglois ldquoRXR acts as a coregulator in the regulation of genes ofthe hypothalamo-pituitary axis by thyroid hormone receptorsrdquoJournal of Molecular Endocrinology vol 29 no 1 pp 61ndash722002

[160] P Lefebvre Y Benomar and B Staels ldquoRetinoid X receptorscommon heterodimerization partners with distinct functionsrdquoTrends in Endocrinology andMetabolism vol 21 no 11 pp 676ndash683 2010

[161] S Mader J Y Chen Z Chen J White P Chambon andH Gronemeyer ldquoThe patterns of binding of RAR RXR andTR homo- and heterodimers to direct repeats are dictated bythe binding specificities of the DNA binding domainsrdquo EMBOJournal vol 12 no 13 pp 5029ndash5041 1993

[162] W R Force J B Tillman C N Sprung and S R SpindlerldquoHomodimer and heterodimer DNA binding and transcrip-tional responsiveness to triiodothyronine (T3) and 9-cis-retinoic acid are determined by the number and order of highaffinity half-sites in a T3 response elementrdquo Journal of BiologicalChemistry vol 269 no 12 pp 8863ndash8871 1994

[163] B Morin L A Nichols and L J Holland ldquoFlanking sequencecomposition differentially affects the binding and functionalcharacteristics of glucocorticoid receptor homo- and het-erodimersrdquo Biochemistry vol 45 no 23 pp 7299ndash7306 2006

[164] T Perlmann P N Rangarajan K Umesono and R M EvansldquoDeterminants for selective RAR and TR recognition of directrepeat HREsrdquo Genes and Development vol 7 no 7 pp 1411ndash1422 1993

[165] R Kurokawa V C Yu A Naar et al ldquoDifferential orientationsof the DNA-binding domain and carboxy-terminal dimeriza-tion interface regulate binding site selection by nuclear receptorheterodimersrdquoGenes and Development B vol 7 no 7 pp 1423ndash1435 1993

[166] R Kurokawa J DiRenzo M Boehm et al ldquoRegulation ofretinoid signalling by receptor polarity and allosteric control ofligand bindingrdquo Nature vol 371 no 6497 pp 528ndash531 1994

[167] A IJpenberg E Jeannin W Wahli and B Desvergne ldquoPolarityand specific sequence requirements of peroxisome proliferator-activated receptor (PPAR)retinoid X receptor heterodimerbinding toDNAA functional analysis of themalic enzyme genePPAR response elementrdquo Journal of Biological Chemistry vol272 no 32 pp 20108ndash20117 1997

[168] J Ferrara K McCuaig G N Hendy M Uskokovic and JH White ldquoHighly potent transcriptional activation by 16-enederivatives of 125- dihydroxyvitamin D3 Lack of modulationby 9-cis-retinoic acid of response to 125-dihydroxyvitamin D3or its derivativesrdquo Journal of Biological Chemistry vol 269 no4 pp 2971ndash2981 1994

[169] B M Forman K Umesono J Chen and R M Evans ldquoUniqueresponse pathways are established by allosteric interactionsamong nuclear hormone receptorsrdquo Cell vol 81 no 4 pp 541ndash550 1995


[170] D Li T Yamada F Wang A I Vulin and H H SamuelsldquoNovel roles of retinoid X receptor (RXR) anal RXR ligand indynamically modulating the activity of the thyroid hormonereceptorRXR heterodimerrdquo Journal of Biological Chemistryvol 279 no 9 pp 7427ndash7437 2004

[171] J Y Chen J Clifford C Zusi et al ldquoTwo distinct actions ofretinoid-receptor ligandsrdquo Nature vol 382 no 6594 pp 819ndash822 1996

[172] S A Kliewer K Umesono D J Noonan R A Heyman and RM Evans ldquoConvergence of 9-cis retinoic acid and peroxisomeproliferator signalling pathways through heterodimer forma-tion of their receptorsrdquo Nature vol 358 no 6389 pp 771ndash7741992

[173] V Antonio B Janvier A Brouillet M Andreani and M Ray-mondjean ldquoOxysterol and 9-cis-retinoic acid stimulate thegroup IIA secretory phospholipase A2 gene in rat smooth-muscle cellsrdquo Biochemical Journal vol 376 no 2 pp 351ndash3602003

[174] I Zamir J Dawson R M Lavinsky C K Glass M GRosenfeld and M A Lazar ldquoCloning and characterizationof a corepressor and potential component of the nuclear hor-mone receptor repression complexrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 94 no26 pp 14400ndash14405 1997

[175] U Dressel D Thormeyer B Altincicek et al ldquoAlien a highlyconserved protein with characteristics of a corepressor formembers of the nuclear hormone receptor superfamilyrdquoMolec-ular and Cellular Biology vol 19 no 5 pp 3383ndash3394 1999

[176] P J Watson L Fairall and J W Schwabe ldquoNuclear hormonereceptor co-repressors structure and functionrdquo Molecular andCellular Endocrinology vol 348 no 2 pp 440ndash449 2012

[177] R P S Kwok J R Lundblad J C Chrivia et al ldquoNuclear proteinCBP is a coactivator for the transcription factor CREBrdquoNaturevol 370 no 6486 pp 223ndash226 1994

[178] J R Lundblad R P S Kwok M E Laurance M L Harter andR H Goodman ldquoAdenoviral E1A-associated protein p300 as afunctional homologue of the transcriptional co-activator CBPrdquoNature vol 374 no 6517 pp 85ndash88 1995

[179] S A Onate S Y Tsai M J Tsai and B W OrsquoMalley ldquoSequenceand characterization of a coactivator for the steroid hormonereceptor superfamilyrdquo Science vol 270 no 5240 pp 1354ndash13571995

[180] J J Voegel M J S Heine C Zechel P Chambon andH Gronemeyer ldquoTIF2 a 160 kDa transcriptional mediatorfor the ligand-dependent activation function AF-2 of nuclearreceptorsrdquo EMBO Journal vol 15 no 14 pp 3667ndash3675 1996

[181] J D Fondell H Ge and R G Roeder ldquoLigand induction of atranscriptionally active thyroid hormone receptor coactivatorcomplexrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 93 no 16 pp 8329ndash8333 1996

[182] X J Yang V V Ogryzko J I Nishikawa B H Howard andY Nakatani ldquoA p300CPB-associated factor that competes withthe adenoviral oncoprotein E1Ardquo Nature vol 382 no 6589 pp319ndash324 1996

[183] A Takeshita G R Cardona N Koibuchi C S Suen and WW Chin ldquoTRAM-1 a novel 160-kDa thyroid hormone receptoractivator molecule exhibits distinct properties from steroidreceptor coactivator-1rdquo Journal of Biological Chemistry vol 272no 44 pp 27629ndash27634 1997

[184] P Puigserver ZWuCW Park RGravesMWright andBMSpiegelman ldquoA cold-inducible coactivator of nuclear receptors

linked to adaptive thermogenesisrdquo Cell vol 92 no 6 pp 829ndash839 1998

[185] C Rachez Z Suldan J Ward et al ldquoA novel protein com-plex that interacts with the vitamin D3 receptor in a ligand-dependentmanner and enhances VDR transactivation in a cell-free systemrdquo Genes and Development vol 12 no 12 pp 1787ndash1800 1998

[186] H J Kim J Y YiH S Sung et al ldquoActivating signal cointegrator1 a novel transcription coactivator of nuclear receptors and itscytosolic localization under conditions of serum deprivationrdquoMolecular and Cellular Biology vol 19 no 9 pp 6323ndash63321999

[187] S K Lee S L Anzick J E Choi et al ldquoA nuclear factor ASC-2 as a cancer-amplified transcriptional coactivator essential forligand-dependent transactivation by nuclear receptors in vivordquoJournal of Biological Chemistry vol 274 no 48 pp 34283ndash34293 1999

[188] Y Wu P Delerive W W Chin and T P Burris ldquoRequirementof helix 1 and the AF-2 domain of the thyroid hormone receptorfor coactivation by PGC-1rdquo Journal of Biological Chemistry vol277 no 11 pp 8898ndash8905 2002

[189] B York and B W OrsquoMalley ldquoSteroid Receptor Coactivator(SRC) family masters of systems biologyrdquo Journal of BiologicalChemistry vol 285 no 50 pp 38743ndash38750 2010

[190] G Salbert A Fanjul F J Piedrafita et al ldquoRetinoic acid recep-tors and retinoid X receptor-120572 down-regulate the transforminggrowth factor-1205731 promoter by antagonizing AP-1 activityrdquoMolecular Endocrinology vol 7 no 10 pp 1347ndash1356 1993

[191] H Harant P J Andrew G S Reddy E Foglar and I JD Lindley ldquo112057225-dihydroxyvitamin D3 and a variety of itsnatural metabolites transcriptionally repress nuclear-factor-120581B-mediated interleukin-8 gene expressionrdquo European Journal ofBiochemistry vol 250 no 1 pp 63ndash71 1997

[192] G Barrera-Hernandez Q Zhan R Wong and S Y ChengldquoThyroid hormone receptor is a negative regulator in p53-mediated signaling pathwaysrdquoDNA and Cell Biology vol 17 no9 pp 743ndash750 1998

[193] J Xu K L Thompson L B Shephard L G Hudson and G NGill ldquoT3 receptor suppression of Sp1-dependent transcriptionfrom the epidermal growth factor receptor promoter via over-lappingDNA-binding sitesrdquo Journal of Biological Chemistry vol268 no 21 pp 16065ndash16073 1993

[194] D DrsquoAmbrosio M Cippitelli M G Cocciolo et al ldquoInhibitionof IL-12 production by 125-dihydroxyvitamin D3 Involvementof NF-120581B downregulation in transcriptional repression of thep40 generdquo Journal of Clinical Investigation vol 101 no 1 pp252ndash262 1998

[195] G B Potter G M J Beaudoin III C L DeRenzo J M ZarachS H Chen and C CThompson ldquoThe hairless gene mutated incongenital hair loss disorders encodes a novel nuclear receptorcorepressorrdquo Genes and Development vol 15 no 20 pp 2687ndash2701 2001

[196] A N Moraitis V Giguere and C C Thompson ldquoNovel mech-anism of nuclear receptor corepressor interaction dictatedby activation function 2 helix determinantsrdquo Molecular andCellular Biology vol 22 no 19 pp 6831ndash6841 2002

[197] J C Hsieh J M Sisk P W Jurutka et al ldquoPhysical and func-tional interaction between the vitamin D receptor and hairlesscorepressor two proteins required for hair cyclingrdquo Journal ofBiological Chemistry vol 278 no 40 pp 38665ndash38674 2003

[198] M T Epping LWangM J Edel L Carlee M Hernandez andR Bernards ldquoThe human tumor antigen PRAME is a dominant


repressor of retinoic acid receptor signalingrdquo Cell vol 122 no6 pp 835ndash847 2005

[199] K Hashimoto M Yamada S Matsumoto T Monden T Satohand M Mori ldquoMouse sterol response element binding protein-1c gene expression is negatively regulated by thyroid hormonerdquoEndocrinology vol 147 no 9 pp 4292ndash4302 2006

[200] J C G Blanco I MWang S Y Tsai et al ldquoTranscription factorTFIIB and the vitaminD receptor cooperatively activate ligand-dependent transcriptionrdquo Proceedings of the National Academyof Sciences of theUnited States of America vol 92 no 5 pp 1535ndash1539 1995

[201] J D Fondell F Brunel K Hisatake and R G Roeder ldquoUnli-ganded thyroid hormone receptor 120572 can target TATA-bindingprotein for transcriptional repressionrdquo Molecular and CellularBiology vol 16 no 1 pp 281ndash287 1996

[202] I J Mcewan and J Gustafsson ldquoInteraction of the humanandrogen receptor transactivation function with the generaltranscription factor TFIIFrdquo Proceedings of the National Academyof Sciences of the United States of America vol 94 no 16 pp8485ndash8490 1997

[203] A Warnmark A Wikstrom A P H Wright J A Gustafssonand T Hard ldquoThe N-terminal Regions of Estrogen Receptor120572 and 120573 are Unstructured in Vitro and Show Different TBPBinding Propertiesrdquo Journal of Biological Chemistry vol 276no 49 pp 45939ndash45944 2001

[204] J Reid I Murray K Watt R Betney and I J McEwanldquoThe androgen receptor interacts with multiple regions of thelarge subunit of general transcription factor TFIIFrdquo Journal ofBiological Chemistry vol 277 no 43 pp 41247ndash41253 2002

[205] S H Khan J Ling and R Kumar ldquoTBP binding-inducedfolding of the Glucocorticoid receptor AF1 domain facilitatesits interaction with Steroid Receptor Coactivator-1rdquo PLoS ONEvol 6 no 7 article e21939 Article ID e21939 2011

[206] D M Heery E Kalkhoven S Hoare and M G ParkerldquoA signature motif in transcriptional co-activators mediatesbinding to nuclear receptorsrdquoNature vol 387 no 6634 pp 733ndash736 1997

[207] A J Bannister and T Kouzarides ldquoThe CBP co-activator is ahistone acetyltransferaserdquo Nature vol 384 no 6610 pp 641ndash643 1996

[208] V V Ogryzko R L Schiltz V Russanova B H Howard and YNakatani ldquoThe transcriptional coactivators p300 and CBP arehistone acetyltransferasesrdquoCell vol 87 no 5 pp 953ndash959 1996

[209] W Shao A Rosenauer K Mann et al ldquoLigand-inducible inter-action of the DRIPTRAP coactivator complex with retinoidreceptors in retinoic acid-sensitive and -resistant acute promye-locytic leukemia cellsrdquo Blood vol 96 no 6 pp 2233ndash22392000

[210] V Perissi L M Staszewski E M McInerney et al ldquoMolecu-lar determinants of nuclear receptor-corepressor interactionrdquoGenes and Development vol 13 no 24 pp 3198ndash3208 1999

[211] P Webb C M Anderson C Valentine et al ldquoThe nuclearreceptor corepressor (N-CoR) contains three isoleucine motifs(ILXXII) that serve as receptor interaction domains (IDs)rdquoMolecular Endocrinology vol 14 no 12 pp 1976ndash1985 2000

[212] M G Guenther O Barak and M A Lazar ldquoThe SMRTand N-CoR corepressors are activating cofactors for histonedeacetylase 3rdquoMolecular and Cellular Biology vol 21 no 18 pp6091ndash6101 2001

[213] A Codina J D Love Y LiM A Lazar DNeuhaus and JW RSchwabe ldquoStructural insights into the interaction and activation

of histone deacetylase 3 by nuclear receptor corepressorsrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 102 no 17 pp 6009ndash6014 2005

[214] M M Montano K Ekena R Delage-Mourroux W ChangP Martini and B S Katzenellenbogen ldquoAn estrogen receptor-selective coregulator that potentiates the effectiveness of antie-strogens and represses the activity of estrogensrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 96 no 12 pp 6947ndash6952 1999

[215] A Mazumdar R A Wang S K Mishra et al ldquoTranscriptionalrepression of oestrogen receptor by metastasis-associated pro-tein 1 corepressorrdquo Nature Cell Biology vol 3 no 1 pp 30ndash372001

[216] N Huang E Vom Baur J M Garnier et al ldquoTwo distinctnuclear receptor interaction domains in NSD1 a novel SETprotein that exhibits characteristics of both corepressors andcoactivatorsrdquo EMBO Journal vol 17 no 12 pp 3398ndash3412 1998

[217] R I Scheinman A Gualberto C M Jewell J A Cidlowskiand A S Baldwin ldquoCharacterization of mechanisms involvedin transrepression of NF-120581B by activated glucocorticoid recep-torsrdquoMolecular and Cellular Biology vol 15 no 2 pp 943ndash9531995

[218] N Yap C L Yu and S Y Cheng ldquoModulation of the tran-scriptional activity of thyroid hormone receptors by the tumorsuppressor p53rdquo Proceedings of the National Academy of Sciencesof the United States of America vol 93 no 9 pp 4273ndash42771996

[219] G G Prefontaine R Walther W Giffin M E LemieuxL Pope and R J G Hache ldquoSelective binding of steroidhormone receptors to octamer transcription factors determinestranscriptional synergism at the mouse mammary tumor viruspromoterrdquo Journal of Biological Chemistry vol 274 no 38 pp26713ndash26719 1999

[220] P Delerive K De Bosscher S Besnard et al ldquoPeroxisomeproliferator-activated receptor 120572 negatively regulates the vas-cular inflammatory gene response by negative cross-talk withtranscription factors NF-120581B and AP-1rdquo Journal of BiologicalChemistry vol 274 no 45 pp 32048ndash32054 1999

[221] L H Wang X Y Yang X Zhang et al ldquoTranscriptionalinactivation of STAT3 by PPARg suppresses IL-6-responsivemultiple myeloma cellsrdquo Immunity vol 20 no 2 pp 205ndash2182004

[222] H P Kim J Y Lee J K Jeong S W Bae H K Lee and IJo ldquoNongenomic stimulation of nitric oxide release by estrogenis mediated by estrogen receptor 120572 localized in caveolaerdquoBiochemical and Biophysical Research Communications vol 263no 1 pp 257ndash262 1999

[223] M L Lu M C Schneider Y Zheng X Zhang and J PRichie ldquoCaveolin-1 interacts with androgen receptor A positivemodulator of androgen receptor mediated transactivationrdquoJournal of Biological Chemistry vol 276 no 16 pp 13442ndash134512001

[224] J A Huhtakangas C J Olivera J E Bishop L P Zanello andA W Norman ldquoThe vitamin D receptor is present in caveolae-enriched plasmamembranes and binds 112057225(OH)

2-vitaminD

3

in vivo and in VitrordquoMolecular Endocrinology vol 18 no 11 pp2660ndash2671 2004

[225] L Matthews A Berry V Ohanian J Ohanian H Garsideand D Ray ldquoCaveolin mediates rapid glucocorticoid effects andcouples glucocorticoid action to the antiproliferative programrdquoMolecular Endocrinology vol 22 no 6 pp 1320ndash1330 2008


[226] S A Mousa L J OrsquoConnor J J Bergh F B Davis T SScanlan and P J Davis ldquoThe proangiogenic action of thyroidhormone analogue GC-1 is initiated at an integrinrdquo Journal ofCardiovascular Pharmacology vol 46 no 3 pp 356ndash360 2005

[227] E Karteris S Zervou Y Pang et al ldquoProgesterone signaling inhuman myometrium through two novel membrane G protein-coupled receptors potential role in functional progesteronewithdrawal at termrdquoMolecular Endocrinology vol 20 no 7 pp1519ndash1534 2006

[228] J L Smith B R Kupchak I Garitaonandia et al ldquoHeterologousexpression of humanmPR120572mPR120573 andmPR120574 in yeast confirmstheir ability to function as membrane progesterone receptorsrdquoSteroids vol 73 no 11 pp 1160ndash1173 2008

[229] A M Nakhla M S Khan and W Rosner ldquoBiologicallyactive steroids activate receptor-bound human sex hormone-binding globulin to cause LNCaP cells to accumulate adenosine31015840

51015840

-monophosphaterdquo Journal of Clinical Endocrinology andMetabolism vol 71 no 2 pp 398ndash404 1990

[230] A M Nakhla J Leonard D J Hryb and W Rosner ldquoSexhormone-binding globulin receptor signal transduction pro-ceeds via a G proteinrdquo Steroids vol 64 no 3 pp 213ndash216 1999

[231] E A Mitchell M B Herd B G Gunn J J Lambert andD Belelli ldquoNeurosteroid modulation of GABAA receptorsmolecular determinants and significance in health and diseaserdquoNeurochemistry International vol 52 no 4-5 pp 588ndash5952008

[232] F Acconcia P Ascenzi A Bocedi et al ldquoPalmitoylation-dependent estrogen receptor 120572 membrane localization regula-tion by 17120573-estradiolrdquo Molecular Biology of the Cell vol 16 no1 pp 231ndash237 2005

[233] L Li M P Haynes and J R Bender ldquoPlasma membranelocalization and function of the estrogen receptor 120572 variant(ER46) in human endothelial cellsrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 100 no8 pp 4807ndash4812 2003

[234] G A Figtree D McDonald H Watkins and K M ChannonldquoTruncated estrogen receptor 120572 46-kDa isoform in humanendothelial cells relationship to acute activation of nitric oxidesynthaserdquo Circulation vol 107 no 1 pp 120ndash126 2003

[235] Z Wang X Zhang P Shen B W Loggie Y Chang and T FDeuel ldquoA variant of estrogen receptor-120572 hER-12057236 transductionof estrogen- and antiestrogen-dependent membrane-initiatedmitogenic signalingrdquo Proceedings of the National Academy ofSciences of the United States of America vol 103 no 24 pp9063ndash9068 2006

[236] M Razandi A Pedram and E R Levin ldquoHeat shock protein 27is required for sex steroid receptor trafficking to and functioningat the plasma membranerdquo Molecular and Cellular Biology vol30 no 13 pp 3249ndash3261 2010

[237] A Pedram M Razandi R J Deschenes and E R LevinldquoDHHC-7 and -21 are palmitoylacyltransferases for sex steroidreceptorsrdquo Molecular Biology of the Cell vol 23 no 1 pp 188ndash199 2012

[238] A Pedram M Razandi R C A Sainson J K Kim C CHughes and E R Levin ldquoA conserved mechanism for steroidreceptor translocation to the plasma membranerdquo Journal ofBiological Chemistry vol 282 no 31 pp 22278ndash22288 2007

[239] G Bondar J Kuo N Hamid and P Micevych ldquoEstradiol-induced estrogen receptor-120572 traffickingrdquo Journal of Neuro-science vol 29 no 48 pp 15323ndash15330 2009

[240] C Buitrago and R Boland ldquoCaveolae and caveolin-1 areimplicated in 112057225(OH)2-vitamin D3-dependent modulation

of Src MAPK cascades and VDR localization in skeletal musclecellsrdquo Journal of Steroid Biochemistry andMolecular Biology vol121 no 1-2 pp 169ndash175 2010

[241] N Bennett J D Hooper C S Lee and G C Gobe ldquoAndrogenreceptor and caveolin-1 in prostate cancerrdquo IUBMB Life vol 61no 10 pp 961ndash970 2009

[242] G Zhao and R U Simpson ldquoMembrane localization Caveolin-3 association and rapid actions of vitamin D receptor in cardiacmyocytesrdquo Steroids vol 75 no 8-9 pp 555ndash559 2010

[243] Z Schwartz H Ehland V L Sylvia et al ldquo112057225-dihydroxyvi-tamin D3 and 24R25-dihydroxyvitamin D3 modulate growthplate chondrocyte physiology via protein kinase C-dependentphosphorylation of extracellular signal-regulated kinase 12mitogen-activated protein kinaserdquo Endocrinology vol 143 no7 pp 2775ndash2786 2002

[244] JMVicencio C IbarraM Estrada et al ldquoTestosterone inducesan intracellular calcium increase by a nongenomic mechanismin cultured rat cardiac myocytesrdquo Endocrinology vol 147 no 3pp 1386ndash1395 2006

[245] N M Storey S Gentile H Ullah et al ldquoRapid signaling at theplasma membrane by a nuclear receptor for thyroid hormonerdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 103 no 13 pp 5197ndash5201 2006

[246] A Zamoner L Heimfarth S O Loureiro C Royer F R M BSilva and R Pessoa-Pureur ldquoNongenomic actions of thyroxinemodulate intermediate filament phosphorylation in cerebralcortex of ratsrdquo Neuroscience vol 156 no 3 pp 640ndash652 2008

[247] K Elbaradie Y Wang B D Boyan and Z Schwartz ldquoRapidmembrane responses to dihydrotestosterone are sex dependentin growth plate chondrocytesrdquo Journal of Steroid Biochemistryand Molecular Biology vol 132 no 1-2 pp 15ndash23 2012

[248] D Menegaz A Barrientos-Duran A Kline et al ldquo112057225(OH)2-

Vitamin D3stimulation of secretion via chloride channel

activation in Sertoli cellsrdquo Journal of Steroid Biochemistry andMolecular Biology vol 119 no 3ndash5 pp 127ndash134 2010

[249] M Druzin E Malinina O Grimsholm and S JohanssonldquoMechanism of estradiol-induced block of voltage-gated K+currents in rat medial preoptic neuronsrdquo PLoS ONE vol 6 no5 article e20213 Article ID e20213 2011

[250] T Simoncini A Hafezi-Moghadam D P Brazil K Ley W WChin and J K Llao ldquoInteraction of oestrogen receptor withthe regulatory subunit of phosphatidylinositol-3-OH kinaserdquoNature vol 407 no 6803 pp 538ndash541 2000

[251] M Pietrzak and M Puzianowska-Kuznicka ldquoTriiodothyro-nine utilizes phosphatidylinositol 3-kinase pathway to activateanti-apoptotic myeloid cell leukemia-1rdquo Journal of MolecularEndocrinology vol 41 no 3-4 pp 177ndash186 2008

[252] T D Yan H Wu H P Zhang et al ldquoOncogenic potential ofretinoic acid receptor g in hepatocellular carcinomardquo CancerResearch vol 70 no 6 pp 2285ndash2295 2010

[253] V Boonyaratanakornkit M P Scott V Ribon et al ldquoPro-gesterone receptor contains a proline-rich motif that directlyinteracts with SH3 domains and activates c-Src family tyrosinekinasesrdquoMolecular Cell vol 8 no 2 pp 269ndash280 2001

[254] AMigliaccio L Varricchio A De Falco et al ldquoInhibition of theSH3 domain-mediated binding of Src to the androgen receptorand its effect on tumor growthrdquo Oncogene vol 26 no 46 pp6619ndash6629 2007

[255] B J Cheskis J Greger N Cooch et al ldquoMNAR plays animportant role in ERa activation of SrcMAPK and PI3KAktsignaling pathwaysrdquo Steroids vol 73 no 9-10 pp 901ndash9052008


[256] J M Garcıa-Pedrero B D Rio C Martınez-Campa MMuramatsu P S Lazo and S Ramos ldquoCalmodulin is a selectivemodulator of estrogen receptorsrdquoMolecular Endocrinology vol16 no 5 pp 947ndash960 2002

[257] L Li Z Li and D B Sacks ldquoThe transcriptional activity ofestrogen receptor-120572 is dependent on Ca2+calmodulinrdquo Journalof Biological Chemistry vol 280 no 13 pp 13097ndash13104 2005

[258] M Hentschke C Schulze U Susens and U Borgmeyer ldquoChar-acterization of calmodulin binding to the orphan nuclear recep-tor ERR120574rdquo Biological Chemistry vol 384 no 3 pp 473ndash4822003

[259] E Cifuentes J M Mataraza B A Yoshida et al ldquoPhysical andfunctional interaction of androgen receptor with calmodulin inprostate cancer cellsrdquo Proceedings of the National Academy ofSciences of the United States of America vol 101 no 2 pp 464ndash469 2004

[260] R Alzamora L R Brown and B J Harvey ldquoDirect bindingand activation of protein kinase C isoforms by aldosterone and17120573-estradiolrdquoMolecular Endocrinology vol 21 no 11 pp 2637ndash2650 2007

[261] R Alzamora and B J Harvey ldquoDirect binding and activation ofprotein kinase C isoforms by steroid hormonesrdquo Steroids vol73 no 9-10 pp 885ndash888 2008

[262] C Demonacos N C Tsawdaroglou R Djordjevic-Markovic etal ldquoImport of the glucocorticoid receptor into rat liver mito-chondria in vivo and in Vitrordquo Journal of Steroid Biochemistryand Molecular Biology vol 46 no 3 pp 401ndash413 1993

[263] C Wrutniak I Cassar-Malek S Marchal et al ldquoA 43-kDaprotein related to c-Erb A 1205721 is located in the mitochondrialmatrix of rat liverrdquo Journal of Biological Chemistry vol 270 no27 pp 16347ndash16354 1995

[264] F Casas L Domenjoud P Rochard et al ldquoA 45 kDa proteinrelated to PPAR1205742 induced by peroxisome proliferators islocated in the mitochondrial matrixrdquo FEBS Letters vol 478 no1-2 pp 4ndash8 2000

[265] J Q Chen M Eshete W L Alworth and J D Yager ldquoBindingof MCF-7 cell mitochondrial proteins and recombinant humanestrogen receptors 120572 and 120573 to human mitochondrial DNAestrogen response elementsrdquo Journal of Cellular Biochemistryvol 93 no 2 pp 358ndash373 2004

[266] S Arnold F Goglia and B Kadenbach ldquo35-Diiodothyroninebinds to subunit Va of cytochrome-c oxidase and abolishes theallosteric inhibition of respiration by ATPrdquo European Journal ofBiochemistry vol 252 no 2 pp 325ndash330 1998

[267] B Notario M Zamora O Vinas and T Mampel ldquoAll-trans-retinoic acid binds to and inhibits adenine nucleotidetranslocase and inducesmitochondrial permeability transitionrdquoMolecular Pharmacology vol 63 no 1 pp 224ndash231 2003

[268] K Sterling and M A Brenner ldquoThyroid hormone actioneffect of triiodothyronine on mitochondrial adenine nucleotidetranslocase in vivo and in VitrordquoMetabolism vol 44 no 2 pp193ndash199 1995

[269] B Lin S K Kolluri F Lin et al ldquoConversion of Bcl-2 fromprotector to killer by interaction with nuclear orphan receptorNur77TR3rdquo Cell vol 116 no 4 pp 527ndash540 2004

[270] A Horvat S Petrovic N Nedeljkovic J V Martinovic and GNikezic ldquoEstradiol affectNa-dependentCa2+ efflux from synap-tosomal mitochondriardquo General Physiology and Biophysics vol19 no 1 pp 59ndash71 2000

[271] N Saelim LM John JWu et al ldquoNontranscriptional modula-tion of intracellular Ca2+ siqnaling by ligand stimulated thyroid

hormone receptorrdquo Journal of Cell Biology vol 167 no 5 pp915ndash924 2004

[272] L Zhang R Zhou X Li R J Ursano andH Li ldquoStress-inducedchange of mitochondria membrane potential regulated bygenomic and non-genomic GR signaling a possiblemechanismfor hippocampus atrophy in PTSDrdquoMedical Hypotheses vol 66no 6 pp 1205ndash1208 2006

[273] M M Poon and L Chen ldquoRetinoic acid-gated sequence-specific translational control by RAR120572rdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 105 no 51 pp 20303ndash20308 2008

[274] F Buttgereit and A Scheffold ldquoRapid glucocorticoid effects onimmune cellsrdquo Steroids vol 67 no 6 pp 529ndash534 2002

[275] L E Panin P V Mokrushnikov V G Kunitsyn and B NZaitsev ldquoInteractionmechanism of cortisol and catecholamineswith structural components of erythrocyte membranesrdquo Jour-nal of Physical Chemistry B vol 114 no 29 pp 9462ndash9473 2010

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


Table 1 Selected representatives of the nuclear receptor superfamily

Family Receptor LigandI Triiodothyronine receptor (TR) Triiodothyronine

Retinoic acid receptor (RAR) All-trans-retinoic acidVitamin D receptor (VDR) 112057225(OH)2D3

Peroxisome-proliferator-activated receptor (PPAR)Polyunsaturated fatty acids benzopyran eicosanoids15-deoxy-1241-prostaglandin J2 thiazolidinedionesother

Reverse-ErbA (Rev-ErbA) UnknownRetinoic-acid-receptor-related orphan receptor (ROR) UnknownLiver X receptor (LXR) Oxysterols

II 9-cis-Retinoic acid receptor (RXR) 9-cis-Retinoic acidHepatocyte nuclear factor-4 (HNF-4) Acyl-CoA thioesters

III

Estrogen receptor (ER) 17120573-estradiolAndrogen receptor (AR) AndrogensProgesterone receptor (PR) ProgesteroneGlucocorticoid receptor (GR) GlucocorticoidsMineralocorticoid receptor (MR) Mineralocorticoids glucocorticoids

IV Nerve-growth-factor-induced clone-B (NGFI-B) UnknownV Steroidogenic factor-1 (SF-1) OxysterolsVI Germ cell nuclear factor (GCNF) Unknown0 Heterodimerization small partner (HSP) Unknown

21 Nuclear Hormone Receptors Nuclear receptors of small-molecule hormones belong to the superfamily of nuclearreceptors consisting of receptors for steroid hormones thy-roid hormone vitamin D retinoic acid and its derivativesfatty acids prostaglandins and cholesterol derivatives aswell as of ldquoorphanrdquo receptors with unknown ligands Smallfractions of some of these receptors also act outside ofthe nucleus in mechanisms generally called ldquonongenomicrdquowhich are mediated by processes other than a direct bindingof the receptor to DNA

Structural similarities of nuclear receptors allow the sub-division of the superfamily into 7 familiessubfamilies (0ndashVI)families I to VI are quite well defined [56ndash58] while family 0contains various receptors which donot fit into other families(Table 1) Nuclear receptors although recognizing their owntarget genes and ligands with high specificity and being eitherpartly or completely devoid of affinity for other genes andligands have a similar structure (Figure 1) A typical full-length nuclear receptor has a variable AB domain at itsN-terminus followed by a well-conserved DNA-binding Cdomain then by a hinge D domain and by a well-conservedligand-binding E domain Some receptors also have an Fdomain on their C-termini the function of which is usuallyunclear

The AB domain of many nuclear receptors containselements involved in hormone-independent transcriptionactivation (AF1) Its function might be modified by phos-phorylation as was shown for the all-trans-retinoic acidreceptor (RAR) peroxisome-proliferator-activated receptor(PPAR) orphan Nurr1 receptor estrogen receptor (ER) and

so forth [59ndash62] The sequence and tridimensional structureof the C domain determine the recognition specificity ofthe receptorrsquos target genes The domain contains two zincfingers in each of them four perfectly conserved cysteineskeep one zinc ion in place [63] At the base of the firstzinc finger a P-box is present its amino acid sequencedetermines the recognition of a specific (usually hexameric)DNA sequence in the receptorrsquos target genes At the baseof the second zinc finger a D-box is located its sequenceis in turn responsible for the recognition of the distancebetween the two hexamers forming the hormone responseelement (HRE) in the promoter of target gene [64] Inaddition the D-box plays a role in receptor dimerizationThe C domain might contain the nuclear localization signal(NLS) or fragments thereof Next the D domain containsNLS and facilitates rotation of the DNA-binding domain inrelation to the ligand-binding domain In addition it containselements involved in cofactor binding DNA binding andin heterodimerization [65] Finally the E domain binds aspecific hormone takes part in homodimerization as well asin heterodimerization and on its C-terminal end containsa ligand-dependent transcription activation domain (AF2)[66] In some cases the E domain might play a role in theactive inhibition of transcriptionThe E domain of the steroidhormone receptors takes part in the binding of heat shockproteins (HSP chaperone) The structure of this domain isformed by 12 120572-helices (H1ndashH12) and resembles pocket-likehormone-binding site The sizes shapes and charges of thispocket present in various receptors differ from each otherand this why most receptors bind only their own hormones


AB C D E

DBD

H

DD DD

NLSNLS

AF1

AF2

AR

DNA-binding domain


Dimerization domain





F













Tran

scrip

tiona

l act

ivity


+HRminusH

+HR +HRminusH

+HRminusHRminus+H



+H +H






HRE

CoABTF

RNA Pol II

SH

HR

SH

SH

HR

HRHSP

HSP

SHSH

SH

HAT

R

HR







2D3 target




HRE

CoRRXR HR

HDAC

HR

R

TF

(a)

HRE

CoABTF

RNA Pol II

HRXRHR

HH

H

HHR

HAT

R

(b)








H

CoA

HAT RNA Pol IIBTF

HRE TATA

HRHR


(a)

CoR

HRE

HR HR

NCoR SMRT

HDAC

CoRNR

(b)

CoR

HDAC

nHRE

HHR HR

RIP140LCoRHrLXXLL

(c)























B

mtDNAHRE

MAPKactivation

AKTactivationp110

PI3K

BTFTFTFRNA Pol II

p28

HHR

HHRHR

HHRH Ca2+

PKAactivation

PKCactivation

IP3

PLC

cAMP

RASMEKERKactivation

A

C

D

E

F

P PP Cytoplasmic

effects

c-SRC

H

H

p85

AC

HR

HR

120572

H













2D3 [240]







2D3 dehy-




Receptor Pathology

























5 Conclusion


References















































































































































































































































2-vitaminD

3








51015840


























































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















AB C D E

DBD

H

DD DD

NLSNLS

AF1

AF2

AR

DNA-binding domain


Dimerization domain





F













Tran

scrip

tiona

l act

ivity


+HRminusH

+HR +HRminusH

+HRminusHRminus+H



+H +H






HRE

CoABTF

RNA Pol II

SH

HR

SH

SH

HR

HRHSP

HSP

SHSH

SH

HAT

R

HR







2D3 target




HRE

CoRRXR HR

HDAC

HR

R

TF

(a)

HRE

CoABTF

RNA Pol II

HRXRHR

HH

H

HHR

HAT

R

(b)








H

CoA

HAT RNA Pol IIBTF

HRE TATA

HRHR


(a)

CoR

HRE

HR HR

NCoR SMRT

HDAC

CoRNR

(b)

CoR

HDAC

nHRE

HHR HR

RIP140LCoRHrLXXLL

(c)























B

mtDNAHRE

MAPKactivation

AKTactivationp110

PI3K

BTFTFTFRNA Pol II

p28

HHR

HHRHR

HHRH Ca2+

PKAactivation

PKCactivation

IP3

PLC

cAMP

RASMEKERKactivation

A

C

D

E

F

P PP Cytoplasmic

effects

c-SRC

H

H

p85

AC

HR

HR

120572

H













2D3 [240]







2D3 dehy-




Receptor Pathology

























5 Conclusion


References















































































































































































































































2-vitaminD

3








51015840


























































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





















Tran

scrip

tiona

l act

ivity


+HRminusH

+HR +HRminusH

+HRminusHRminus+H



+H +H






HRE

CoABTF

RNA Pol II

SH

HR

SH

SH

HR

HRHSP

HSP

SHSH

SH

HAT

R

HR







2D3 target




HRE

CoRRXR HR

HDAC

HR

R

TF

(a)

HRE

CoABTF

RNA Pol II

HRXRHR

HH

H

HHR

HAT

R

(b)








H

CoA

HAT RNA Pol IIBTF

HRE TATA

HRHR


(a)

CoR

HRE

HR HR

NCoR SMRT

HDAC

CoRNR

(b)

CoR

HDAC

nHRE

HHR HR

RIP140LCoRHrLXXLL

(c)























B

mtDNAHRE

MAPKactivation

AKTactivationp110

PI3K

BTFTFTFRNA Pol II

p28

HHR

HHRHR

HHRH Ca2+

PKAactivation

PKCactivation

IP3

PLC

cAMP

RASMEKERKactivation

A

C

D

E

F

P PP Cytoplasmic

effects

c-SRC

H

H

p85

AC

HR

HR

120572

H













2D3 [240]







2D3 dehy-




Receptor Pathology

























5 Conclusion


References















































































































































































































































2-vitaminD

3








51015840


























































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















HRE

CoABTF

RNA Pol II

SH

HR

SH

SH

HR

HRHSP

HSP

SHSH

SH

HAT

R

HR







2D3 target




HRE

CoRRXR HR

HDAC

HR

R

TF

(a)

HRE

CoABTF

RNA Pol II

HRXRHR

HH

H

HHR

HAT

R

(b)








H

CoA

HAT RNA Pol IIBTF

HRE TATA

HRHR


(a)

CoR

HRE

HR HR

NCoR SMRT

HDAC

CoRNR

(b)

CoR

HDAC

nHRE

HHR HR

RIP140LCoRHrLXXLL

(c)























B

mtDNAHRE

MAPKactivation

AKTactivationp110

PI3K

BTFTFTFRNA Pol II

p28

HHR

HHRHR

HHRH Ca2+

PKAactivation

PKCactivation

IP3

PLC

cAMP

RASMEKERKactivation

A

C

D

E

F

P PP Cytoplasmic

effects

c-SRC

H

H

p85

AC

HR

HR

120572

H













2D3 [240]







2D3 dehy-




Receptor Pathology

























5 Conclusion


References















































































































































































































































2-vitaminD

3








51015840


























































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















HRE

CoRRXR HR

HDAC

HR

R

TF

(a)

HRE

CoABTF

RNA Pol II

HRXRHR

HH

H

HHR

HAT

R

(b)








H

CoA

HAT RNA Pol IIBTF

HRE TATA

HRHR


(a)

CoR

HRE

HR HR

NCoR SMRT

HDAC

CoRNR

(b)

CoR

HDAC

nHRE

HHR HR

RIP140LCoRHrLXXLL

(c)























B

mtDNAHRE

MAPKactivation

AKTactivationp110

PI3K

BTFTFTFRNA Pol II

p28

HHR

HHRHR

HHRH Ca2+

PKAactivation

PKCactivation

IP3

PLC

cAMP

RASMEKERKactivation

A

C

D

E

F

P PP Cytoplasmic

effects

c-SRC

H

H

p85

AC

HR

HR

120572

H













2D3 [240]







2D3 dehy-




Receptor Pathology

























5 Conclusion


References















































































































































































































































2-vitaminD

3








51015840


























































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















H

CoA

HAT RNA Pol IIBTF

HRE TATA

HRHR


(a)

CoR

HRE

HR HR

NCoR SMRT

HDAC

CoRNR

(b)

CoR

HDAC

nHRE

HHR HR

RIP140LCoRHrLXXLL

(c)























B

mtDNAHRE

MAPKactivation

AKTactivationp110

PI3K

BTFTFTFRNA Pol II

p28

HHR

HHRHR

HHRH Ca2+

PKAactivation

PKCactivation

IP3

PLC

cAMP

RASMEKERKactivation

A

C

D

E

F

P PP Cytoplasmic

effects

c-SRC

H

H

p85

AC

HR

HR

120572

H













2D3 [240]







2D3 dehy-




Receptor Pathology

























5 Conclusion


References















































































































































































































































2-vitaminD

3








51015840


























































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
































B

mtDNAHRE

MAPKactivation

AKTactivationp110

PI3K

BTFTFTFRNA Pol II

p28

HHR

HHRHR

HHRH Ca2+

PKAactivation

PKCactivation

IP3

PLC

cAMP

RASMEKERKactivation

A

C

D

E

F

P PP Cytoplasmic

effects

c-SRC

H

H

p85

AC

HR

HR

120572

H













2D3 [240]







2D3 dehy-




Receptor Pathology

























5 Conclusion


References















































































































































































































































2-vitaminD

3








51015840


























































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





















2D3 [240]







2D3 dehy-




Receptor Pathology

























5 Conclusion


References















































































































































































































































2-vitaminD

3








51015840


























































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


















Receptor Pathology

























5 Conclusion


References















































































































































































































































2-vitaminD

3








51015840


























































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





















5 Conclusion


References















































































































































































































































2-vitaminD

3








51015840


























































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of














































































































































































































































2-vitaminD

3








51015840


























































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





















51015840


























































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of











































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















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