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2023年4月1日发(作者：安徽大学教务处网站)

AndrogenReceptor(AR)Coregulators:ADiversityof

FunctionsConvergingonandRegulatingtheAR

TranscriptionalComplex

DepartmentsofUrologyResearch,Biochemistry,andMolecularBiology,MayoClinic,Rochester,Minnesota55905

Androgens,actingthroughtheandrogenreceptor(AR),are

responsibleforthedevelopmentofthemalephenotypeduring

embryogenesis,theachievementofsexualmaturationatpu-

berty,andthemaintenanceofmalereproductivefunctionand

tion,androgensaffectawide

er,aberrantan-

drogenactionplaysacriticalroleinmultiplepathologies,

includingprostatecancerandandrogeninsensitivitysyn-

mationofaproductiveARtranscriptional

complexrequiresthefunctionalandstructuralinteractionof

astdecade,anoverwhelm-

ingandeverincreasingnumberofproteinshavebeenpro-

posedtopossessARcoactivatingorcorepressingcharacter-

uingly,avastdiversityoffunctionshasbeen

ascribedtotheseproteins,indicatingthatamultitudeofcel-

lularfunctionsandsignalsconvergeontheARtoregulateits

rentreviewaimstoprovideanoverviewof

theARcoregulatorproteinsidentifiedtodateandtopropose

aclassificationoftheseARcoregulatorproteinsaccordingto

thefunction(s)ogether,thisap-

proachwillincreaseourunderstandingofthecellularpath-

waysthatconvergeontheARtoensureanappropriatetran-

scriptionalresponsetoandrogens.(EndocrineReviews28:

778–808,2007)

uction

rogenReceptor(AR)

-InteractingProteins

ltranscriptionfactors

gulators

ictranscriptionfactors

ationsandSignificanceoftheConvergenceofaMul-

titudeofDiverseFunctionsontheAR

tetranscriptionaloutputbytheARrequiresthecon-

certedactionofnumerouscellularpathwaysandprocesses

lyoftheARtranscriptionalcomplex

odationofcoregulatorsbytheAR

gulatorsin(Patho)Physiology

sionsandFutureDirections

uctionANDROGENS,WHICHAREthemainmalesexsteroids,

areresponsibleforthedevelopmentofthemalephe-

notypeduringembryogenesisandformalesexualmatura-

thood,androgensremainessentialfor

FirstPublishedOnlineOctober16,2007

Abbreviations:ADI,Androgendepletionindependent;AF,activation

function;ANPK,AR-interactingnuclearproteinkinase;ANT-1,AR

N-terminaldomaintransactivatingprotein-1;AR,androgenreceptor;

ARA,AR-associated;ARE,androgenreponseelement;ARIP,AR-inter-

actingprotein;ARNIP,ARN-terminal-interactingprotein;ARR19,AR

corepressor19kDa;ART-27,AR-trappedclone27;Asc,activatingsignal

cointegrator;BAF,BRG1-associatedfactor;BRG1,Brahma-relatedgene

1;CARM-1,coactivator-associatedargininemethyltransferase1;CBP,

CREB-bindingprotein;CDK6,cyclin-dependentkinase6;Chip,C-ter-

minalHsp-interactingprotein;ChIP,chromatinimmunoprecipitation;

CTD,COOHterminaldomain;DBD,DNA-bindingdomain;DHEA,

dehydroepiandrosterone;DHT,dihydrotestosterone;DJBP,DJ-1-bind-

ingprotein;DNA-PK,DNA-dependentproteinkinase;E6-AP,E6-

associatedprotein;FHL2,four-and-a-half-LIM-onlyprotein2;FKBP52,

FK506bindingproteinof52kDa;GAK,G-associatedkinase;GDI,gua-

ninenucleotidedissociationinhibitor;GSK-3␤,glycogensynthaseki-

nase-3␤;HAT,histoneacetylase;HBO1,humanoriginrecognitioncom-

plexinteractingprotein;hBRM,humanhomologofDrosophilabrmgene;

HBx,hepatitisBvirusnonstructuralproteinx;HDAC,histonedeacety-

lase;Hey,Hairy/EnhancerofsplitrelatedwithYRPWmotif;HIP1,

huntingtin-interactingprotein1;HPV,humanpapillomavirus;Hsp,

heatshockprotein;LBD,ligand-bindingdomain;LIM,LIN-11,ISL-1,

andMEC-3;LSD1,lysine-specificdemethylase1;MAK,malegermcell-

associatedkinase;MKRN1,MakorinRINGzincfingerprotein1;MNAR,

modulatorofnongenomicactionsoftheestrogenreceptor;NCoR,nu-

clearreceptorcorepressor;NLS,nuclearlocalizationsignal;NTD,N-

terminaldomain;PAK,p21-activatedkinase;PCa,prostatecancer;

P/CAF,p300/CBP-associatedfactor;PELP1,proline-,glutamicacid-,

andleucine-richprotein-1;PIAS,proteininhibitorsofactivatedSTAT;

PIC,preinitiationcomplex;PKC,proteinkinaseC;PKN,proteinkinase

N;p54nrb,p54nuclearRNAbindingprotein;PP2A,proteinphospha-

tase2A;PRK,PKC-relatedkinase;PRMT,proteinargininemethyltrans-

ferase;PSA,prostatespecificantigen;PSF,polypyrimidinetract-binding

protein-associatedsplicingfactor;PSP,paraspeckleprotein;p-TEFb,

positivetranscriptionelongationfactorb;RACK1,receptorforactivated

Ckinase1;RanBPM,Ran-bindingproteininthemicrotubule-organizing

center;Rb,retinoblastomaprotein;RSK,ribosomalS6kinase;SCP,small

CTDphosphatase;SENP1,SUMO1/sentrin-specificprotease1;siRNA,

smallinterferingRNA;SIRT1,Sirtuin1;SMRT,silencingmediatorof

retinoidandthyroidreceptors;SNURF,smallnuclearRINGfingerpro-

tein;SRA,steroidreceptorRNAactivator;SRC,steroidreceptorcoac-

tivator;SRCAP,SNF2-relatedCBPactivatorprotein;SRG,SW13-related

geneproduct;ST,smalltantigen;STAT,signaltransducerandactivator

oftranscription;SUMO,smallubiquitin-relatedmodifier;SWI/SNF,

matingtypeswitching/sucrosenonfermenting;TAU,transactivation

unit;TBP,TATA-bindingprotein;TIF,transcriptionalintermediaryfac-

tor;Tip60,Tatinteractiveprotein60kDa;TSG101,tumorsusceptibility

gene101;Uba3,ubiquitin-activatingenzyme3;Zac1,zinc-fingerprotein

whichregulatesapoptosisandcellcyclearrest1.

EndocrineReviewsispublishedbyTheEndocrineSociety(

),theforemostprofessionalsocietyservingthe

endocrinecommunity.

0163-769X/07/$20.00/0EndocrineReviews28(7):778–808

ght2007byTheEndocrineSociety

doi:10.1210/er.2007-0019

778

byonJanuary7,nloadedfrom

themaintenanceofmalereproductivefunctionandbehavior.

Inadditiontotheireffectsonreproduction,androgensaffect

awidevarietyofnonreproductivetissuesincludingskin,

bone,muscle,sequence,de-

regulationsintheproductionoractionofandrogenscan

affectdifferentorgansystemswithavariabledegreeofse-

reflectedinpathologiesrangingfromandro-

geninsensitivitysyndromesandprostatecancertoanin-

creasedriskandsusceptibilitytogender-relateddiseases

suchashepatocellularcarcinomas,torelativelymildcondi-

tionssuchasacneandmalepatternalopecia(1–6).

Testosterone,theprincipalandrogeninthemalecircula-

tion,ainingandrogens

inthebloodstream[5–10%,includingdehydroepiandros-

terone(DHEA),androstenediol,andandrostenedione]are

eitherproducedbytheadrenalcortexandcanbeconverted

intotestosteroneinperipheraltissuesorarederivedfrom

peripheralconversionfromtestosterone[dihydrotestoster-

one(DHT)](7–8).Synthesisofandrogensistightlyregulated

ilesecre-

tionofLHRHbythehypothalamusstimulatessecretionof

LHbytheanteriorpituitary,whichinturninducesproduc-

ter-

oneactsthroughanegativefeedbacklooptopreventLHRH

releasebythehypothalamusandtodecreasethesensitivity

orityofcirculatingtestos-

teroneisboundtocarrierproteins:-

fore,only1–2%oftestosteroneexistsinanunbound,free

orandrogensinwomenincludeDHEAsulfate,

DHEA,androstenedione,testosterone,en

biosynthesisoccursinboththeadrenalandtheovary,and

itisregulatedbyACTH(adrenalsynthesis)andLH(ovarian

synthesis)(9,10).

Upontransportationbythebloodtoitstargettissues,

unbound,lipophilictestosteronediffusesintoitstargetcell

whereitcanberapidlyandirreversiblyconvertedintoits

morepotentmetaboliteDHTbyactionof5␣-reductasein

somebutnotalltargetcells(typeIorII,dependingonthe

targettissue)(11).BothtestosteroneandDHT(eitherlocally

producedorfromthecirculation)exerttheiractivitiesby

bindingtoacognatereceptor,theandrogenreceptor(AR),a

110-kDamemberofthenuclearreceptorsuperfamilyofli-

dstheARwith

higheraffinity,anditsbiologicalactivityexceedsthatof

testosteroneupto10times(12).DHTdissociatesfromtheAR

moreslowlythantestosterone,andARboundtoDHTis

morestable,persistingincellsforgreaterlengthsoftime(13).

Initsbasal,unligandedstate,theARresidesprimarilyinthe

cytoplasmiccompartmentwhereitexistsinacomplexwith

heatshockproteins(Hsps)andimmunophilinchaperones

suchasHsp70,90,56,gandbinding,alter-

ationsoccurinthecompositionofthisHspcomplex,andthe

ARundergoesaconformationalchange,allowingnuclear

translocationoftheARandARhomodimerformation(14).

Insidethenucleus,theactivatedARbindstospecificrecog-

nitionsequencesknownasandrogenreponseelements

(AREs)inthepromoterandenhancerregionsoftargetgenes.

TheARE-boundARdimercaneitherinteractdirectlywith

componentsofthetranscriptionpreinitiationcomplexor

recruitothercomponentsthatpromotesuchafunctional

interaction(15–17).Recruitedelementsmaybeothertran-

scriptionfactorsbindingtorecognitionelementsinthevi-

cinityofAREsandformingmorecomplexandrogenre-

sponseunits,

generaldefinition,ARcoregulatorsareproteinsthatarere-

cruitedbytheARandeitherenhance(vators)or

reduce(essors)itstransactivation,buttheydonot

significantlyalterthebasaltranscriptionrateanddonot

d,coregulators

influenceAR-mediatedtranscriptionbyactingatthetarget

genepromoterregiontofacilitateDNAoccupancy,chroma-

tinremodeling,and/orrecruitmentofgeneraltranscription

factorsassociatedwithRNApolymeraseII,orbyassuring

thecompetencyoftheARtoenhancegeneexpressiondi-

tercanbeachievedbymodulationoftheproper

foldingoftheAR,ensuringitsstabilityorcorrectsubcellular

localization(16,17).Inthelastdecade,anoverwhelmingand

everincreasingnumberofproteinshavebeenidentifiedas

urrentreview,weprovideanover-

viewoftheARcoregulatorsthathavebeenidentifiedtodate.

Inviewoftheremarkablefunctionaldiversitydisplayedby

theseproteinsandthevastnumberofcellularpathwaysin

whichtheyareinvolved,weproposeaclassificationofAR

coregulatoryproteinsaccordingtotheirintrinsicprimary

y,wediscusstheimportanceofthesefactors

intheregulationoftissue-selectiveandrogen-dependent

geneexpressionunderphysiologicalandpathological

conditions.

rogenReceptor(AR)

Likeothermembersofthenuclearreceptorsuperfamily,

theARischaracterizedbyamodularstructureconsistingof

fourfunctionaldomains:anN-terminaldomain(NTD),a

DNA-bindingdomain(DBD),ahingeregion,andaligand-

bindingdomain(LBD)(18,19).TheARNTDisrelatively

longanddisplaysthemostsequencevariabilityamongnu-

ryflexibleanddisplaysahighdegree

ofintrinsicdisorder,whichhashamperedstudiesintoits

three-dimensionalstructure(20).TheARNTDcontainsthe

majortransactivationfunctionoftheAR,termedactivation

function(AF)paratedfromtheLBD,AF-1gives

ifsintheARNTD,

23-FQNLF-27andtoalesserextent433-WHTLF-473,have

beenshowntointeractwiththeLBD,resultinginanNH

COOHterminalintra-and/orintermolecularARinteraction

thathasbeenproposedtobeimportantforthetranscrip-

tionalactivationofsome,butnotall,ARtargetgenes(21).

AF-1ishighlymodularandconsistsoftwotransactivation

units(TAUs),TAU1andTAU5,thatparticipateintran-

scriptionalactivation(22).TheAF-1domainundergoesin-

ducedfoldingwhencontactedbybasaltranscriptionfactors

suchasTFIIF,resultinginamorecompactandactivecon-

formationthatenablesfurthercoregulatorrecruitmentand

transcription(20).Inaddition,theNTDharborsavariable

numberofhomopolymericrepeats,themostimportantof

whichisapolyglutaminerepeatthatrangesfrom8to31

repeatsinnormalindividuals,withanaveragelengthof20.

Expansionoftheglutaminerepeatsupto40residuesormore

HeemersandTindall•FunctionallyDiverseARCoregulatorsEndocrineReviews,December2007,28(7):778–808779

byonJanuary7,nloadedfrom

resultsinspinalandbulbarmuscularathrophy(SBMAor

Kennedy’sdisease),anX-linkedpathologycharacterizedby

neurologicalfeaturesandlateonsetsymptomsofmildan-

drogeninsensitivity(1,23,24).Shorteningofthepolyglu-

taminestretch,ontheotherhand,givesrisetoamoretran-

scriptionallyactiveAR,whichhasbeensuggestedtobe

associatedwithapredispositiontoprostaticneoplasia(25).

ThecentrallylocatedDBDisthemostconservedregion

gionharborsnine

cysteineresidues,ofwhicheightareinvolvedinformingtwo

zincfingers,stzincfinger,

mostproximaltotheNTD,determinesthespecificityofDNA

recognition,whereasresiduesinthesecondzincfingerare

onomersinahead-

to-headconformationbindasahomodimertoAREs(26),

whicharedirectorindirectrepeatsofthecore5-TGTTCT-3,

ormorecomplexresponseelementsharboringdiversear-

rangementsofAREs(27,28).TheC-terminalextensionis

importantfortheoverallthree-dimensionalstructureofthe

DBDandplaysaroleinmediatingtheARselectivityofDNA

interaction(27).

Thehingeregionhaslongbeenconsideredtobeaflexible

cently,however,

thisregionwasshowntobeinvolvedinDNAbindingaswell

asARdimerizationandwassuggestedtoattenuatetran-

scriptionalactivityoftheAR(29,30).Moreover,aligand-

dependentbipartitenuclearlocalizationsignal(NLS)islo-

catedinthecarboxyterminalpartoftheDBDandthehinge

region,implicatingthehingeregioninARnucleartranslo-

cation(31,32).

X-raycrystallographicstudiesindicatethattheARLBD

structureissimilartothatoftheothermembersofthenuclear

receptorsuperfamily(33–36).TheLBDinnuclearreceptors

consistsof12discrete␣-ionoftheagonistinto

theARligand-bindingpockethasbeensuggestedtochange

theconformationoftheLBDinsuchawaythathelix-12is

adstotheformationofashallowhydro-

phobicgrooveatthetopoftheligandbindingpocket,gen-

-2isthemajorprotein-protein

interactionsurfaceusedbynuclearreceptorstorecruit

LXXLL-motifcontainingcoactivators(37).TheAR,however,

differsfromothernuclearreceptorsinthisrespectandin-

ro-

phobicpocketintheAR-LBDbindspreferentiallytoFXXLF

motifs,includingthe23-FQNLF-27foundinitsNTD,and

interactspoorlywithLXXLLmotifscommonlyfoundinco-

activators(38–42).Consequently,thehydrophobicpocket

withintheARLBDfacilitatesintramolecularandintermo-

lecularinteractionbetweentheARNTDanditsCterminus

andisapparentlynotreadilyavailableforcoactivatorbind-

datasuggestthattheARN/Cterminalinterac-

tionsoccurpredominantlywhentheARisnotboundto

DNA(43).Interestingly,severalAR-associatedcoactivators

thatcontainFXXLFmotifshavebeenisolated(44),suggest-

ingthatcompetitionexistsbetweentheseregulatoryproteins

licationsof

suchcompetitionandtheassociationofNTDandLBDare

notclear,butsuggestthatadditionalsurfacesoutsidethis

well-definedcoactivatorpocketenabletheARtointeract

withitscoactivatorsandthatdifferentclassesofcoactivators

bservations

explainwhytheAF-2intheARLBDdisplaysrelativelyweak

ligand-dependenttransactivatingpropertieswhencom-

eless,

mutationordeletionofAF-2markedlyreducestranscrip-

romforming

theligandbindingpocket,theARLBDmediatesinteraction

betweentheARandHsps(14).

-InteractingProteins

Ingeneral,proteinsthatinteractwiththeARcanbedi-

videdintothreegeneralclasses:1)componentsofthegeneral

transcriptionalmachinery;2)functionallydiverseproteins

withARcoactivatingorcorepressingproperties;and3)spe-

gulatorsdifferfromgen-

eralandspecifictranscriptionfactorsinthattheydonot

affectthebasalrateoftranscriptionandtypicallydonotbind

toDNA.

ltranscriptionfactors

Asisthecaseforothertranscriptionfactors,enhanced

transcriptionbytheARdependsontherecruitmentofRNA

achievedbytheassemblyofgeneraltranscriptionfactorsthat

makeupthepreinitiationcomplex(PIC).Adetaileddescrip-

tionoftranscriptioninitiationisbeyondthescopeofthis

manuscriptandhasbeenreviewedpreviously(45).Briefly,

formationofthePICisaccomplishedbybindingofTFIID,

whichiscomposedofTATA-bindingprotein(TBP)andTBP-

associatedfactors,intheproximityofthetranscriptionalstart

henbindsTBPandrecruitsRNApolymeraseII

andTFIIF,whichensuresspecificinteractionofRNApoly-

ndTFIIHarerecruitedto

RNApolymeraseIItofacilitatestrandseparation,which

ghmanyAR-associ-

atedcoregulatorsfacilitateandmediatecommunicationbe-

tweentheARandthegeneraltranscriptionalmachinery,the

ARhasalsobeenshowntointeractdirectlywithcomponents

tance,theAR

NTDinteractswithRAP74,g

ofRAP74induces␣-helicalstructureinAF-1andfacilitates

interactionbetweentheARandthep160coactivatorsteroid

receptorcoactivator(SRC)-1(20,46–50).Modestbindingto

theRAP30subunitofTFIIFandTBPhasalsobeendescribed

(46).Moreover,theARhasbeenshowntointeractwith

TFIIH,andoverexpressionofthecdk-activatingkinasesub-

unitofTFIIHmarkedlystimulatestheAR-mediatedtran-

scription(50).theARinteractionwithTFIIHmayenhance

phosphorylationoftheRNApolymeraseCOOHterminal

domain(CTD),aneventnecessarytotransitionfromtran-

scriptioninitiationtotranscriptionalelongation,suggesting

thattheARmayincreasetheefficiencyoftranscriptional

tentwiththishypoth-

esis,aninteractionbetweentheARandpositivetranscription

elongationfactorb(p-TEFb)hasbeendescribed(51).The

smallsubunitofp-TEFb,PITALRE(alsoknownasCDK9),

harborsproteinkinaseactivitythatisabletophosphorylate

theCTDofthelargestsubunitofRNApolymeraseII,which

780EndocrineReviews,December2007,28(7):778–808HeemersandTindall•FunctionallyDiverseARCoregulators

byonJanuary7,nloadedfrom

isnecessarytoprogressfromPICformationonthepromoter

ably,bothTFIIHand

p-TEFbpossessCTDkinaseactivity,buttheseactivitiesact

atdifferentstagesoftranscrip26个字母背诵顺口溜 tion(15).Inadditiontoits

contactswithseveralgeneraltranscriptionfactors,theAR

alsointeractsdirectlywithRNApolymeraseIIthroughas-

essionofRPB2,

whichisinvolvedintranscriptionalelongation,stimulates

AR-mediatedtranscriptionoftargetgenes(52).Interactionof

theARwithandregulationofAR-mediatedgeneexpression

byothersubunitsofRNApolymeraseIIhasnotbeenob-

ogether,thesefindingsindicatethattheAR

mayregulatetranscriptionoftargetgenesbyregulatingboth

transcriptionalinitiationandelongationevents.

gulators

Morethan200nuclearreceptorcoregulatorshavebeen

identifiedsincetheisolationofthefirstnuclearreceptor

coactivator,SRC-1,in1995(53).Byminingpeer-reviewed

literatureaccessiblethroughPubMed()

andconsultingspecializedwebsitesdedicatedtoARfunc-

tion[theARgenemutationdatabase()

andtheNuclearReceptorSignalingAtlas(NURSA)database

()],wehaveattemptedtoprovideanup-to-

dateoverviewofproteinsthathavebeenlistedasputative

y2007,thelistofproteins

thathavebeenclassifiedaspotentialARcoregulatorscon-

ably,thesecoregulatorsdisplay

adiversearrayoffunctionsandareinvolvedinmultiple

remanywaysonecouldcatego-

chosentoarrangethese

thefunctionforwhichtheyarebestrecognized,evenif,in

somecases,thisparticularactivitymaynotbecriticalfor

l,wefeelthatsuchaclas-

sification,ratherthanclassificationbytheirfunctionasa

coactivatororacorepressor,willprovideabroaderpicture

ofthecellulareventsthatconvergeonandregulatethetrans-

bediscussedbelow,

thisdoesnotprecludethepossibilitythatsomemultifunc-

tionalARcoregulatorscanbeassignedtomultiplecatego-

sonsofsimplicityandtokeepouroverview

comprehensive,wechosenottoincludeinformationonthe

specificcellsystemsorspecifictargetgenesusedtoascertain

thecoregulatorpropertiesoftheARcofactorsinthissection.

ThisinformationwillbeaddressedinSectionsIVandV.

rip-

tionoccursonachromatintemplate,inwhichDNAiswound

aroundacoreoffourbasichistoneproteins(H2A,H2B,H3,

andH4)-histoneinteractions

limittheaccessibilityofthenucleosomalDNAtotranscrip-

matinremodelingcomplexesalterandunwrapthehistone-

DNAcontactsinanATP-dependentmannercatalyzedby

ATPases,leadingtoreorganizationofthenucleosomalstruc-

tureandeventuallytoachromatinstatusthatismoreper-

missivetotranscription(54,55).SeveralARcoregulatorpro-

teinshavebeenidentifiedascomponentsofthechromatin

hefirstindicationsthatcom-

ponentsofthechromatinremodelingcomplexmayplaya

roleinAR-mediatedtranscriptioncamefromtheidentifica-

tionofAR-interactingprotein(ARIP)4,anuclearATPase

thatbelongstotheSNF2-likefamilyofchromatinremodeling

4interactswiththeARzinc-fingerregionand

stimulatesAR-dependenttransactivationincotransfection

experiments(56).AlhoughARIP4displaysDNA-dependent

ATPaseactivity,itsspecificactivitywassubsequentlyshown

tobeconsiderablylowerthanthatofSNF2-familymembers,

suggestingthatitmaynotbeaclassicalchromatinremod-

eless,ARIP4mutantsthatdonotpos-

sessATPaseactivitybehaveasdominant-negativeregulators

ofARfunction(56,57).Subsequently,theATPasesBrahma-

relatedgene1(BRG1)andhumanhomologofDrosophilabrm

gene(hBRM),twocorecomponentsrequiredfornucleosome

repositioningbythematingtypeswitching/sucrosenonfer-

menting(SWI/SNF)chromatinremodelingcomplex,were

showntostimulateARactivitypotently(58).Dependingon

thegenecontext,however,differentrequirementsforthese

ATPaseswerenoted,withsomegenesrelyingsolelyon

hBRMandothersrelyingonbothhBRMandBRG1foran-

drogenregulation(58).TheBRG1-associatedfactor(BAF)57

subunit,anaccessorycomponentofthisremodelingcom-

plex,isalsorequiredforAR-dependenttransactivation(59).

TheARcoactivationfunctionofBAF57dependsonSWI/

SNFATPaseactivityandcooperateswithotherclassesof

57directlybindstotheARandisrecruited

toARtargetgenesuponligandstimulation(59).Interest-

ingly,theSWI3-relatedgeneproduct(SRG3/BAF155),an-

othercomponentoftheSWI/SNFcomplex,isalsoableto

3interactswiththe

ARDBD-hingeregionandexistsinacomplexwiththeAR

onpromotersofARtargetsgenes(60).SRG3appearsto

initiateatleastsomeofitscoactivationpropertiesbyenlisting

ably,SRG3functionmaynot

beentirelydependentonthepresenceofBRG1orhBRM(60).

Furthermore,theSNF2-relatedCREB-bindingprotein(CBP)

activatorprotein(SRCAP)isabletocoactivatetranscription

bytheAR(61).DirectinteractionofSRCAPwiththeAR,

however,rly,hOsa1(BAF250)

andhOsa2,thelargestsubunitsoftheSWI/SNFcomplex,

stimulatetranscriptionbytheAR,butassociationofthese

proteinswiththeARhasnotbeendemonstrated(62).

Overall,therecruitmentofthesechromatinremodeling

proteinstotheARtranscriptionalcomplexisconsistentwith

thealteredDNAtopologyandthelossofcanonicalnucleo-

somalladderthatisobservedatARtargetgenesafterex-

posuretoandrogens(63).

emodifiers:-

ditiontochromatinremodeling,whichrepresentsahigher

orderlevelofchromatinreorganizationandinvolvesrepo-

sitioningofcomponentsofthenucleosomestructure,mod-

ificationofhistoneresiduescanaffecttranscriptionefficiency

andprovideamorelocalizedcontrolovertranscriptional

eventsinchromatin(54,55).Modificationssuchasacetyla-

tion,methylation,phosphorylation,ubiquitination,ADP-ri-

bosylation,andglycosylationofhistoneresidueshavebeen

cases,modificationofahistoneresidue

HeemersandTindall•FunctionallyDiverseARCoregulatorsEndocrineReviews,December2007,28(7):778–808781

byonJanuary7,nloadedfrom

changesthenetchargeofthenucleosome,whichresultsin

example,acetylationofahistonelysineresidueattenuatesits

posititivechargeandabrogatesitsinteractionwiththeneg-

thesehistonemodifications

,acetyla-

tion),andothersareindicativeofactiveorrepressedgenes

(ation).Also,thepositionofthemodifiedhistone

cept

thatacombinationofsuchmarksaffectsbindingoftran-

scriptionallyeffectorproteinsliesatthebasisofthehistone

code(54,55).

Inkeepingwiththisnotion,severaldynamicchangesin

thecovalenthistonemodificationstatushavebeenassociated

ncludeacti-

vatingmodificationsathistone3suchasacetylationoflysine

9andlysine14,dimethylationofarginine17,phosphoryla-

tionofserine10,anddimethylationaswellastrimethylation

oflysine4(64).Inaddition,removalofrepressivemarkshas

beendescribed,suchasdemethylationofmono-,di-,and

trimethylmarksatlysine9ofhistone3anddecreaseinthe

dimethylationstatusoflysine20athistone4(65–68).The

significanceofthesemodificationswillbediscussedinmore

detailinsectionsofthetextdescribingenzymesexecuting

ryofthehistonemodificationsasso-

ciatedwithandrogenactioncanbefoundinFig.1.

Recruitmentofhistoneacetylase(HAT)activitytochro-

versely,deacetylationofthesemarksbyhistonedeacetylase

(HDAC)activityrendersthechromatinenvironmenttran-

lHATsandHDACshave

beenshowntointeractwiththeARandmodulateitstrans-

activatingproperties.

Forexample,twomembersofthep160SRCgenefamily,

SRC-1andSRC-3[p300/CBPinteractingprotein(p/CIP),

receptor-associatedcoactivator-3(RAC3),acetyltransferase

(ACTR),amplifiedinbreastcancer-1(AIB1),orthyroidhor-

monereceptoractivatormolecule-1(TRAM1)]havebeen

rtoSRC-2[also

knownasglucocorticoidreceptor-interactingprotein-1or

transcriptionalintermediaryfactor(TIF)-2],thethirdmem-

berofthisfamilythatdoesnotpossessHATactivity,SRC-1

andSRC-3interactdirectlyandligand-dependentlywiththe

ARtoenhanceAR-mediatedtranscription(16,53,69–77).

AlthoughtheLXXLLmotif-containingp160familymembers

havebeenshowntointeractwithARAF-2,theyinteract

primarilywiththeARNterminusandpossiblytheDBD.

Moreover,allthreeSRCfamilymembersfunctionasscaffold

proteinsthatattractadditionalcoactivatorproteins,includ-

ingfactorswithhistone-modifyingpotential(78).Indeed,

SRCshavebeenshowntorecruitp300,thep300homolog

CBP,aswellasp300/CBP-associatedfactor(P/CAF),all

coactivatorproteinsthatpossessHATfunctionsthatare

intrinsicallystrongerthanthosefoundinSRC-1and-3.

Moreover,invitroexperimentshavedemonstratedadirect,

SRC-independentinteractionbetweenp300,CBP,and

P/CAFandtheAR(79).Thepotentiationofligand-induced

ARtransactivationbythesethreecoactivators(79–81)relies

tionto

theireffectsonhistones,CBP,p300,andP/CAFcanacetylate

worthy,p300,aswellasP/CAF,acetylatestheARatthree

lysineresiduesinitsDBD-hingeregion(79).Pointmutations

intheseARacetylationsitesselectivelypreventandrogen

inductionofandrogen-responsivegenes,hampercoactiva-

tionoftheARbySRC-1,p300,Tip60,andUbc9,andresult

ina10-foldincreaseinthebindingofthecorepressornuclear

receptorcorepressor(NCoR)(81).Itshould,however,be

notedthatthelysineresiduesthatareacetylatedbyp300and

P/CAFarepartoftheARNLSandthatmutationsofthese

sitesmaythereforebeexpectedtodisruptARactivityre-

eless,

histoneacetylationbyp300andCBPfacilitatesrecruitment

oftheSWI/SNFandMediatorcoactivatorcomplexes(63).

Furthermore,CBPandp300functionasadirectbridgebe-

tweenDNA-boundARandthebasaltranscriptionalma-

chinery(79).Theymayalsoserveasascaffoldinteracting

withandassemblinganumberofothertranscriptionalreg-

ulators(79).

AnothercoregulatorthatharborsHATactivityisTatin-

teractiveprotein60kDa(Tip60).Tip60interactswiththeAR

LBDandenhancesAR-mediatedtranscriptionbyacetylating

ationofARlysineresidues

intheAR-hingeregionbyTip60isarequisiteforTip60-

ably,actionof

Tip60onARtransactivationiscounteractedbyHDAC1

(82–84).

Humanoriginrecognitioncomplexinteractingprotein

(HBO1)isanotherHATproteinthatliganddependently

rytothe

HATproteinslistedabove,HBO1actsasanARcorepressor,

inhibitinghormone-dependentARactivation(85).Thedirect

involvementoftheHATfunctionofHBO1intheseeventsis

ARE

DHT

+androgens

ACTIVATIONDEREPRESSION

+ac-H3K9-mono-me-H3K9

+ac-H3K14-di-me-H3K9

+di-me-H3R17-tri-me-H3K9

+phos-H3S10-di-me-H4-K20

+di-me-H3K4

+tri-me-H3K4

nthistonemodificationsassociatedwithandrogen

action.

782EndocrineReviews,December2007,28(7):778–808HeemersandTindall•FunctionallyDiverseARCoregulators

byonJanuary7,nloadedfrom

notclear,becauseHBO1hasbeenreportedtoharborarel-

er,histoneacetylationby

ore,HBO1hasbeen

proposedtoacetylatehistonesaspartofamultisubunitcom-

plex(86).

Theimportanceofacetylationanddeacetylationofhistone

andnonhistoneproteinsinAR-mediatedtranscriptionisfur-

theremphasizedbythefunctionalantagonismbetweenthe

nicotinamideadeninedinucleotide-dependentHDACSir-

tuin1(SIRT1)(andp300atsitesofARacetylation).SIRT1

(Sir2,aclassIIIHDAC)repressesandrogen-inducedAR

signalingbyamechanismthatinvolvesdirectbindingtothe

ARhingeandrequiresboththenicotinamideadeninedinu-

cleotide-dependentcatalyticfunctionofSIRT1anddeacety-

lationofthelysineresidues630/632/633intheAR-hinge

regionthataretargetedbyp300andP/CAF(87).Moreover,

SIRT1inhibitsp300-mediatedinteractionbetweentheARN

therhand,ligand-inducedrepression

ofARfunctionbytheclassIIHDACHDAC7isindependent

er,thedeacetylaseactivity

ofHDAC7isatleastpartlydispensableintherepressionof

ARfunction(88).InadditiontoSIRT1,severalHDACsof

toSIRT1andHDAC7,whichcaninteractdirectlywiththe

AR,recruitmentofHDACstotheARtranscriptionalcom-

plexisusuallyindirectthroughassociationwithmultisub-

unitcorepressorcomplexessuchasNCoRandsilencingme-

diatorofretinoidandthyroidreceptors(SMRT)orasbinding

partnersforotherARcorepressors(17).

ReflectingtheimportanceoftheactionofHATsand

HDACenzymesatgenomicsitesmediatingARtranscrip-

tionalactivity,theacetylationstatusofhistone3and4res-

iduesisoftenassessedasamarkerforthetranscriptional

activationstatusofaparticularARtargetgene.

emodifiers:-

thoughhistoneacetylationisgenerallyassociatedwithactive

genetranscription,histonemethylationcanbeindicativeof

boththeactiveandrepressedtranscriptionalstatesofthe

chromatin(54,55).Thepositionofthehistoneresidueaf-

fectedbythismodificationisimportantformakingthisdis-

mple,methylationoflysine4onhistone3;

arginines2,17,and26onhistone3;andarginine3onhistone

4isassociatedwithactivegenes,whereasmethylationof

lysine9onhistone4ispredominantlyassociatedwithre-

er,lysineresiduescanbemono-

methylated,dimethylated,ortrimethylated,andtheextentof

themethylationservesasanimportantindicationofitstran-

ghmethylationhaslongbeencon-

sideredtobeanirreversibleepigeneticmark,recently,dem-

ethylasesthatmediateactivedemethylationofrepressive

histonesegmentshavebeenidentified(54,55).

AR-dependenttranscriptionreliesonbothmethyltrans-

vator-associatedar-

gininemethyltransferase1(CARM-1)orproteinarginine

methyltransferase(PRMT)-5,ahistonemethyltransferase

actingatH3R17,wasidentifiedinitiallybyitsabilityto

tsindirectrecruit-

menttoligand-boundnuclearreceptorsincludingtheAR,

CARM-1hasbeenclassifiedasasecondarycoactivator(89).

AndrogenstimulationleadstorecruitmentofCARM-1to

androgen-responsiveenhancers(90).CARM-1stimulationof

ARtransactivationdependsentirelyonthepresenceofSRC

er,thepresenceofCARM-1en-

CARM-1reducestranscriptionofandrogen-responsive

onofitsS-adenosylmethioninebindingsite

abrogatesitsmethyltransferaseactivityandprevents

tion

toitseffectsonhistones,CARM-1methylatesproteinsinthe

transcriptionalcomplexincludingCBP/p300andseveral

RNAbindingproteins(89,90).Noteworthy,CARM-1may

alsoberecruitedtotheARtranscriptionalcomplexthrough

p44(MEP50),acomponentofthemethylosome.p44interacts

directlywiththe轻易的近义词 ARandCARM-1,isfoundonpromotersof

ARtargetgenesuponandrogenstimulation,andstimulates

tion,p44

andCARM-1synergisticallycooperatetoenhancetransac-

tivationbytheAR(91).SimilartoCARM-1,PRMT1isre-

cruitedtotheARtranscriptionalcomplexandstimulates

AR-dependentgeneexpressionviaSRCproteins(92).

PRMT1,however,preferentiallymethylatesH4R3,which

facilitatessubsequentacetylationofhistone4tailsbyp300.

Remarkably,acetylationofhistone4inhibitsitsmethylation

RM-1,PRMT1dependsonanintact

S-adenosylmethioninebindingsitetofulfillitscofactor

function.

Methylationoflysine9onhistone3bythemethyltrans-

feraseG9aispredominantlyassociatedwithrepressionof

r,forsomenuclearreceptorsinclud-

ingtheAR,G9afunctionsasacoactivator,althoughweakly

(93).Nonetheless,G9acooperatessynergisticallywithTIF-2,

CARM-1,andp300inactivatingtranscriptionbytheAR.

Thissynergyisstronglydependentonthearginine-specific

proteinmethyltransferaseactivityofCARM-1,suggestinga

linkbetweenhistonearginineandlysinemethylationinAR-

rthy,PRMTmethyltrans-

otherhand,cooperationbetweenG9a,CARM-1,andSRC-2

doesnotabsolutelyrequiretheenzymaticactivityofG9a.

ThedependencyofG9aonSRC-2indicatesthatSRC-2may

functionasascaffoldtorecruitG9a.G9aassociateswith

regulatoryregionsinARtargetgenesinthepresenceaswell

astheabsenceofandrogens,andlossofG9aexpression

hampersandrogen-inducedAR-dependentstimulationof

targetgenes(93).

Recently,histonemethyltransferaseactivitywithaspec-

ificityforH3-K36andH4-K20hasbeenattributedtonuclear

receptor-bindingSu(var)3-9,Enhancer-of-zeste,Trithorax

(SET)domain-containingprotein-1(NSD1,alsoknownas

AR-associated(ARA)protein267␣)(94).Basedonitsability

tointeractwiththeARDBD-LBDregion,tos唐诗宋词赏析 timulateAR

transactivationinanandrogen-dependentmanner,andto

cooperatewithotherARcoregulators,ARA267hasbeen

classifiedasanAR-associatedcoactivator(95).Althoughthis

possibilityremainstobeproven,itistemptingtospeculate

thattheAR-coactivatingpropertiesofARA267aremediated

byitshistonemethyltransferasemoiety.

Theconceptthatdemethylationofhistonesisinvolvedin

transcriptionalactivationbytheARhasemergedonlyre-

HeemersandTindall•FunctionallyDiverseARCoregulatorsEndocrineReviews,December2007,28(7):778–808783

byonJanuary7,nloadedfrom

stwastriggeredbytheobservationthatlysine-

specificdemethylase1(LSD1),whichspecificallydemeth-

ylatesmonomethylatedanddimethylatedH3K9,interacts

withtheAR(NTD,DBD,aswellasLBD),andstimulates

AR-dependenttranscription(65).Down-regulationofLSD1

expressionabrogatesandrogen-inducedtranscriptionalac-

tinimmunoprecipitation(ChIP)analysis

demonstratedthatARandLSD1formchromatin-associated

enexpo-

sureleadstoarobustdecreaseinmono-,di-,andtrimethyl

terferingRNA(siRNA)-mediatedlossofLSD1preventsli-

gand-inducedchangesinmono-anddimethylH3K9but

doesnotaffecttrimethylH3K9(65).SimilartoLSD1,

JHDM2A,whichdemethylatesmono-anddimethylated

H3K9,interactsdirectlywiththeARandcoactivatesandro-

gen-mediatedtranscription(66).ContrarytoLSD1,which

isconstitutivelypresentatARtargetgenes,JHDM2Aex-

pressionof

JHDM2AgreatlyreducestheH3K9methylationlevel.A

knockdownofJHDM2Aexpressionresultsinincreaseddi-

methylK9levelsatthepromoterregionofARtargetgenes

LSD1doesnotaffectthebindingoftheARtopromoter

regionsoftargetgenesortheligand-inducedrecuitmentof

JHDM2A,butitdoespartiallyimpairhormone-inducedre-

ductionofdimethylH3K9(66).InadditiontoLSD1and

JHDM2A,athirddemethylase,JMJD2C,interactswithand

functionsasacoactivatorfortheAR(67).Interestingly,

JMJD2Cisahistonetridemethylaseabletoremovemono-,

di-,D1,JMJD2Cis

constitutivelypresentatpromoterregionsofARtarget

JD2CandLSD1interactwithandstimulate

AR-dependentgenetranscriptioninacooperativemanner.

Uponandrogentreatment,AR,LSD1,andJMJD2Cassemble

onchromatin,resultingindemethylationofmono-,di-,and

trimethylH3K9andstimulationofAR-dependenttranscrip-

sely,knockdownofJMJD2Cinhibitsandrogen-

inducedremovaloftrimethylH3K9andtranscriptionalac-

tivationbytheAR(67).Takentogether,theseobservations

indicatethatandrogen-dependentgenetranscriptionre-

quirestheassemblyandcoordinateactionofmethyltrans-

ferasesanddemethylaseswithdistinctsubstratespecificities.

entsoftheubiquitination/-

uitinationisareversibleposttranslationalmodificationof

cellularproteinsinwhicha76-aminoacidpolypeptide,ubiq-

uitin,tination

ofasubstrateinvolvestheactionofanactivatingE1enzyme

thattransfersubiquitintoaconjugatingE2enzyme,whichin

turnenlistsanE3ligasetodelivertheubiquitintagtothe

proteinscanbeeitherpoly-

merusually

servesasasignalfordegradationofthesubstrateproteinby

the26Sproteasome,whereasthelattertendstofunctionas

asignalthatregulatesproteinstabilityandprotein-protein

recognition,activity,

modesofubiquitinationplayvitalrolesintranscriptional

regulationbecausetheyallowproperprogressionthrough

roundsoftranscriptionandappropriateassemblyofthe

necessaryproteincomplexes,andtheymodulatetheactiva-

tionstatusoftranscriptionfactorsandcoregulators(96,97).

Notsurprisingly,severalARcoregulatorproteinsfunctionin

thesecoregula-

torsdemonstrateE3ligaseactivity;thisisthecaseforin-

stanceforE6-AP,Mdm2,PIRH2,SNURF/RNF4andChip.

TheE3ligaseE6-associatedprotein(E6-AP)interactswith

theARNTDinahormone-dependentmanner,demonstrates

hormone-dependentrecruitmenttothepromoterregionof

ARtargetgenes,andenhancesthetransactivationfunction

oftheAR(98).E6-APmayalsomodulatetheproteinlevelof

theARbecauseE6-APnullmicedemonstrateincreasedAR

levelsinandrogen-responsiveprostatetissues,andoverex-

pressionofE6-APmarkedlyreducesARproteinexpression

incellsinculture(98).Inaddition,Mdm2interactswiththe

interactionofMdm2withtheARNTDandDBDisatleast

inpartdependentonitsE3ubiquitinligaseactivity(99).

Afterandrogenstimulation,Mdm2complexeswiththeAR

andHDAC1atactiveARtargetgenepromotersandatten-

eARandHDAC1areubiquitinated

1andMdm2cooperateto

reduceAR-mediatedtranscription,andthisfunctionalin-

teractionisattenuatedbytheHATactivityoftheARcoac-

tivatorTip60(100).Thissuggestsaninterplaybetweenacet-

ylationstatusandreceptorubiquitylationinARregulation.

Supportingthispossibility,Tip60alsointeractswithPIRH2,

rtoMdm2,PIRH2interactsdi-

rectlywiththeAR(NTD)andHDAC1(101).However,

PIRH2enhancesAR-mediatedtranscriptionbyreducing

HDAC1proteinlevelsandinhibitionofHDAC1-mediated

2isrecruitedtoAREsinAR

targetgenesandisrequiredforoptimalexpressionofthese

3ubiquitinligasesmallnuclearRINGfinger

protein(SNURF/RNF4)wasisolatedasanARcoregulator

basedonitsabilitytointeractwiththeARNLSinahormone-

dependentmanner(102).SNURFdoesnotinfluencethe

bindingoftheARtocognateDNAsequences,butitappears

toenhancetransactivationbytheARbyfacilitatingitsimport

intothecellnucleus(103).SNURFalsoretardsARnuclear

exportonhormonewithdrawal(104).Todate,thereisno

evidenceofSNURF-mediatedchangesintheubiquitination

tiontoitsE3ubiquitinligasefunc-

tion,C-terminalHsp-interactingprotein(Chip)actsasamo-

lecularchaperoneinvolvedinthefoldingandhormonebind-

ctionbetweenChipandthe

ARNTD,whichoccursinahighlyspecificandsequence-

dependentmanner,suggestsafunctionallinkbetweenthese

processesintheregulationofARactivity(105).Chipnega-

tivelyregulatesARtranscriptionalactivitybypromotingAR

ubiquitinationanddegradation(105,106).Noteworthy,

theseeffectsofChiparenotfullyreversedbyproteasome

inhibitors,suggestingthatmechanismsdifferentfrompro-

,Chip

overexpressionreducestherateofARdegradation,whichis

consistentwithaneffectonARfolding(107).Thus,itseffect

onARactionmightnotbeentirelydependentonitsubiquitin

ligaseactivity.

OtherproteinsthathavebeenidentifiedasARcoregula-

torsandhavebeensuggestedtopossessE3ubiquitinligase

784EndocrineReviews,December2007,28(7):778–808HeemersandTindall•FunctionallyDiverseARCoregulators

byonJanuary7,nloadedfrom

functionareARNIP,ARA54andMKRN1(108–111).AR

N-terminal-interactingprotein(ARNIP)interactswiththe

ARNTD,althoughitdoesnotaffectARligand-bindingki-

r,ARN-ter-

minal-C-terminalinteractionisreducedinthepresenceof

ARNIP(108).ARA54hasbeenisolatedbasedonitsabilityto

ligand-dependentlyassociatewiththeARLBDandwassub-

sequentlyshowntoenhanceAR-mediatedtransactivation

(109).TheubiquitouslyexpressedMakorinRINGzincfinger

protein1(MKRN1)inhibitsthetranscriptionalactivityofthe

AR(111).Interestingly,disruptionoftheubiquitinligase

activityofMKRN1doesnotaffectitsinhibitorytranscrip-

rARNIP,ARA54,andMKRN1affect

theubiquitinationstatusoftheARoritsassociatedcomplex

hasnotbeenassessed.

InadditiontotheseE3ubiquitinligases,proteinswith

otherfunctionsintheubiquitin/proteasomepathwayhave

instance,theubiquitin-specificproteaseUSP10interactsdi-

rectlywiththeARandispartofDNA-boundARcomplexes

(112).USP10,butnotanenzymaticallyinactivemutant

USP10,sely,

lossofUSP10expressionimpairsresponsivenesstoandro-

rly,theE2ubiquitin-conjugatingenzyme

UBCH7stimulatesAR-mediatedtransactivationinahor-

mone-dependentmanner(113).Theubiquitinconjugation

us-

ceptibilitygene101(TSG101),anE2-likeenzymedeprivedof

ubiquitinconjugaseactivity,whichhasbeenproposedtoact

asadominant-negativeinhibitorofpolyubiquitination,also

101was

originallyshowntorepressligand-dependentARtranscrip-

tionalactivation(114).Interestingly,inanindependentstudy

TSG101wasreportedtoactasacoactivatorforAR-mediated

transcription(115).TSG101enhancesmonoubiquitinationof

theARinaligand-dependentmanner,andthiscorrelates

ant-nega-

tivemutantofubiquitinpreventingpolyubiquitinationalso

stimulatesAR-mediatedtranscription,whichcannotbeen-

hancedbyTSG101(115).

Thesereportsestablishmultipleeffectorsofdistinctsteps

intheubiquitinylationpathwayasimportantregulatorsof

stingly,theroleofthe

proteasomeintheseeventsdoesnotappeartoberestricted

solelytodegradationoftheARoritsassociatedproteinsin

thecytoplasm(Ref.116,andalsodiscussedbelow).Instead,

theproteasomeitselfmaybeactivelyinvolvedinAR-gov-

poth-

esisissupportedbytheobservationthatoverexpressionof

theproteosomalsubunitPSMA7enhancesARtransactiva-

tion(117).Moreover,inhibitionoftheproteasomeprevents

thenucleartranslocationoftheAR,blocksinteractionbe-

tweentheARandseveralofitscoregulators,andultimately

abolishesandrogen-inducedtargetgeneexpression(117).In

addition,afterandrogentreatment,the19Sproteasomalsub-

complexisrecruitedtoARtargetgenes,whereitsoccupancy

parallelsthatoftheAR(118).

llubiquitin-

relatedmodifierSUMOposttranscriptionallymodifiessev-

eralproteinsinvolvedinregulationoftranscriptionand

hineryresponsibleforthe

sumoylationoftargetgenesdisplaysremarkablesimilarity

tothatmediatingproteinubiquitinationbecauseitconsists

ofE1-activatingenzymes,anE2-conjugatingenzyme,and

1,-2,and-3enzymesare,how-

ever,distinctfromtheircounterpartenzymesintheubiq-

uitin/rtothenon-proteasomal

rolesofubiquitin,SUMOmodificationofaproteinprimarily

regulateslocalizationandactivity(119).Multipleproteins

involvedinseveralaspectsofthesumoylationpathwaycan

,SUMOhomologs

havebeenshowntoaffectAR-mediatedtranscription.

SUMO-1decreases,whereasSUMO-2and-3enhanceAR

transcriptionalactivity(120,121).SUMO-3interactswiththe

itiveeffectofSUMO-3onAR-transcrip-

tionalactivitydoesnotdependoneitherthesumoylation

sitesoftheARorthesumoylationfunctionofSUMO-3(121).

SumoylationoftheARNTDbySUMO-1isstimulatedby

androgens,andmutationofthesumoylationsitesintheAR

NTDincreasesARtransactivation,indicatingthatsumoyla-

tionservestoattenuateARfunction(120).Second,theSUMO

E2conjugatingenzymeUbc9interactswiththeNLSinthe

AR-hingeregionandactsasaARcoactivator(122).Inter-

estingly,theeffectsofUbc9onARactivityoccurindepen-

dentlyofitsSUMO-1conjugatingcatalyticactivity(122,123).

Third,proteininhibitorsofactivatedSTAT(PIAS)family

membersthatfunctionasSUMOE3ligasescaneitherpos-

itivelyornegativelyaffecttranscriptionbytheAR(124–132).

PIASproteins(PIAS-1,-3,-x

␣,orARIP3,-x␤,and-y)bindthe

ARDBD(126).Althoughhomologous,PIASproteinscan

differmarkedlyintheirabilitytosumoylatetheARand/or

AR-associatedcoactivatorssuchasTIF-2(131).PIAS-y,

whichactsasacorepressorfortheAR,doesnotrelyonits

E3ligaseactivitytoinfluenceAR-mediatedtranscription

(132).Moreover,thedecisionforaparticularPIASproteinto

functionasacorepressororcoactivatordependsonthecell

typeandthetargetgene(127).Furthermore,thePIAS-like

SUMOE3ligasesZimp7andZimp10bothfunctionasAR

coactivators(133–135).Zimp10wasshowntointeractwith

theARNTD(133).ARsumoylationisenhancedinthepres-

enceofZimp10,andmutationoftheARsumoylationsites

abrogatestheaugmentationofARactivitybyZimp10(133,

135).Fourth,AR-mediatedtranscriptionismarkedlyen-

hancedbySENP1,amemberoftheSUMO-specificprotease

family(136).AlthoughtheARisatargetforSENP1,the

abilityofSUMO1/sentrin-specificprotease1(SENP1)toen-

hanceAR-dependenttranscriptionisnotmediatedthrough

desumoylationoftheAR,butratherthroughitsabilityto

deconjugateHDAC1,therebyreducingitsdeacetylaseac-

ressiveeffectofHDAC1onAR-dependent

transcriptioncanbereversedbySENP1andbydeletionof

rast,SENP2andSENP3have

onlymodesteffectsonARtransactivation(136).

Inadditiontotheubiquitination/proteasomeandsumoy-

lationpathways,activityoftherelatedneddylationpathway

uitin-activatingenzyme3(Uba3),thecatalyticsubunitofthe

activatingenzymeoftheubiquitin-likeNEDD8(neuralpre-

cursorcellexpresseddevelopmentallydown-regulated)con-

HeemersandTindall•FunctionallyDiverseARCoregulatorsEndocrineReviews,December2007,28(7):778–808785

byonJanuary7,nloadedfrom

jugationpathway,

neddylationactivityofUba3isrequiredforitsinhibitionof

interactionbetween

Uba3andtheARhasnotbeenreported(137).

Overall,theidenti激变的拼音 ficationofnumerousproteinswithfunc-

tionsintheubiquitination,SUMOylationaswellas

NEDDylationpathwaysasARcoregulatorspointstoward

thecriticalimportanceoftightregulationoftheturnover,

stability,degradation,andsubcellularrelocalizationofcom-

ponentsoftheARtranscriptionalmachineryinandrogen-

regulatedgenetranscription.

transcriptsundergoseveralmodificationsbeforeamature

mRNAisgeneratedthatcanserveasatemplatefortrans-

ethestepsfromtranscriptiontotranslationare

mechanisticallyandfunctionallycoupled(138,139),itisnot

surprisingthatseveralproteins,whichdemonstrateARco-

regulatorcharacteristics,belongtoorsharehighfunctional

orstructuralhomologytomembersofthefamilyofRNA

tance,thepre-mRNAsplicing

proteinsPSF(polypyrimidinetract-bindingprotein-associ-

atedsplicingfactor),PSP1(paraspeckleprotein1)andPSP2

interactwithAF-1oftheAR(140).p54nrb(p54nuclearRNA

bindingprotein,NonO),anothercomponentoftheU1snRNP

prespliceasome,interactswiththeARNTDinaligand-de-

pendentmannerandpotentiatesAF-1function(140).Be-

causep54nrbandPSFalsodirectlyinteractwiththeRNA

polymeraseIICTD,amolecularlinkbetweentheARtran-

scriptionalandsplicingmachineryisapparent(138).Fur-

thermore,p102U5snRNPhasbeenisolatedasaproteinin-

teractingwithARAF-1,termedANT-1(ARN-terminal

domaintransactivatingprotein-1).ANT-1enhancestheli-

gand-independentAF-1functionoftheARbutdoesnot

affectligand-dependentAF-2activity(141,142).

ThesplicingfactorhnRNPA1isrecruitedtotheAR

throughassociationwiththeARinteractingcoactivator

ARA54andselectivelysuppressesARA54-enhancedAR

transactivationviainterruptionofAR-ARA54interaction

(143).Finally,thepreviouslydiscussedmethyltransferases

CARM-1andp44(MEP50)arecomponentsofthemethylo-

somecomplexthatmethylatessnRNPcomplexproteins,sug-

gestingthattheyalsofulfillrolesinsplicingevents.

getedapproachto

discovercomponentsthatcomprisetheARapo-andholo-

receptorcomplexusingtandemmassspectroscopyanalysis,

thetrimericDNA-dependentproteinkinase(DNA-PK)com-

plexwasisolated(144).TheDNA-PKcomplexisbestknown

foritsroleinDNArepairandhasemergedasapartofthe

-LBDinteractsdirectly

withtheKu70andKu80regulatorysubunitsofDNA-PKin

ctionbetweentheAR

proteinsbindtheARinboththecytoplasmandthenucleus.

Kuproteinsarerecruitedinanandrogen-dependentmanner

70andKu80aswell

asDNA-PKenhanceARactivityintransactivationassays.

Ku70andKu80havebeenshowntoexerttheseeffects

throughrecyclingoftranscriptionalfactors(144).Otherpro-

teinswithrolesinDNArepairanddamagecontrolhavebeen

instance,thecheckpointproteinRad9actsasacorepressorto

suppressARtransactivation(145).TheARinteractswiththe

LFmotifwithinthe

CterminusofRad9interruptstheandrogen-inducedinter-

actionbetweentheNterminusandCterminusoftheAR.

Moreover,thetumorsuppressorgenesBRCA1andBRCA2

areARcoactivators(146–148).BRCA2isanintegralcom-

ponentofthehomologousrecombinationmachinery,

whereasBRCA1possessesbothE3ubiquitinligaseactivity

1interactswiththeARNTD

1-en-

hancedARtransactivationcanbefurtherinducedsynergis-

ticallywithARcoregulatorsSRCs,CBP,ARA55,andARA70

(146,147).BRCA2,butnotatruncatedmutantofBRCA2,

synergizeswithSRC-2toenhancetranscriptionalactivation

2associateswiththeARNTDandLBD,as

wellasSRC-2,andfurthercooperateswithP/CAFand

BRCA1toenhanceAR-andSRC-2-mediatedtransactivation

(148).

Ingeneral,componentsoftheDNArepairmachineryare

recruitedwhenthetranscriptionalmachineryrunsintoob-

staclesorDNAlesionsthatpreventpropertranscriptionof

ntificationofseveralproteinswithfunc-

tionsinDNArepairascoregulatorsfortheARindicatesthat

thismechanismholdstruealsoforAR-mediatedtranscription.

bsenceofandrogens,

themolecularchaperonecomplexiscriticaltomaintainthe

ARinastable,inactive,intermediateconfigurationthathas

ndingofan-

drogensandfoldingoftheARintoanactiveconformation,

selectivemolecularchaperonesremainassociatedwiththe

ARandareimportantfordownstreameventssuchasAR

translocation,ARtranscriptionalactivity,disassemblyofthe

ARtranscriptionalcomplex,-

tainedimportanceoftheseproteinsinoverallARactivityis

reflectedintheinteractionsbetweentheARandmultiple

componentsofchaperonecomplexesthroughoutthelifecy-

cleoftheAR(14).IntheearlystagesoftheARactivation

process,ARLBDinteractstransientlywithHsp40(Ydj1),

Hsp70(HSc70),Hip,Hps90,Hop,andp23,leadingtoan

equilibriuminwhichtheARismaintainedinanoverall

respect,Hsp40is

necessaryforhormonebindingtotheAR(149).Mutationsin

Hsp40resultinareductionofAR-Hsp70complexformation

anddefectsinARfolding(150).Incontrast,lossoftheHsp70

cochaperoneDjA1inaknockoutmousemodelleadstoin-

creasesinARproteinlevelsandenhancedtranscriptionof

severalandrogen-responsivegenesinSertolicells,givingrise

toseveredefectsinspermatogenesis(151).Inthesamestudy,

DjA1wassuggestedtofunctionasanegativeregulatorof

ebindingcausestheAR

toundergoasequentiallossofchaperones(14).Withthe

assistanceofHsp90,theARistransformedintoaDNA-

oractivationleadstoun-

maskingoftheNLS,resultinginHsp90-dependenttranslo-

cationoftheARtothenucleus(14).Cdc37(p50)also

functionsdown-streamofhormone-bindingasanHsp90-

786EndocrineReviews,December2007,28(7):778–808HeemersandTindall•FunctionallyDiverseARCoregulators

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forms

ofcdc37inducedefectsinARtransactivationwhileleaving

ARproteinlevelsunaltered(152).Hsp70andHsp40arealso

believedtoreassociatewiththeARinthepresenceofligand

andtofacilitatetransportofthereceptorintothenucleus(14).

Hsp90bindingcochaperoneFKBP52(FK506bindingprotein

of52kDa)interactswithARcomplexes(153).Invivostudies

usingFKBP52-deficientmiceindicatethatFKBP52doesnot

affecthormonebindingbytheARorARnucleartransloca-

tionbutiscriticalforARtransactivation(153,154).FKBP52

enhancesAR-mediatedtranscription,andthiseffectdepends

onitsabilitytointeractwithHsp90(153).FKBP52mayalso

benecessarytomaintainARproteinlevels(153).Therelated

cochaperoneFKBP51formscomplexeswiththeARandstim-

ulatesARtransactivation,althoughtheseobservationscould

notbeconfirmedbyasecond,independentstudy(154,155).

ApartfromtheireffectsonARfoldingandtrafficking,ex-

perimentalevidencesupportsadirectinvolvementofmo-

lecularchaperonesinthetranscriptionalactivationofAR

-1Hsp70cochaperones,inparticularthe

Bag-1Lisoform,binddirectlytotheTAU5domainintheAR

NTDandfunctionasacoactivatorfortheAR(156,157).

Bag-1LreliesonitsassociationwithHsp70tointeractwith

theAR,andlossofthisinteractiondomainmarkedlysup-

pressesitsabilititytostimulateAR-mediatedtransactivation.

Moreover,Bag-1LaswellasHsp70arerecuitedwiththeAR

topromoterregionsofARtargetgenes(156).Noteworthy,

Bag-1Lharborsaubiquitin-likedomainthatfacilitatesasso-

ciationofBag-1Lwiththeproteasome,enablingBag-1Lto

functionasacouplingfactorbetweenthechaperoneand

proteolyticcomplex(158).Thisisremine杜甫石壕吏写作背景 scentofthedual

func烟花易冷 tionofChipasbothanE3ubiquitinligaseandaco-

,ARdegradationbyanHsp70-Chipgov-

ernedsystemhasbeenreported(158).Bag-1andChipin-

teractdirectlyandcooperatewitheachotherduringthe

together,thesefindingssuggestaninterdependencybe-

tweenAR-mediatedtranscription,ARdegradation,andfold-

ingevents.

samajorcomponentofthe

ghthecytoplasmicrolesofactinand

actinorganizationinthecytoplasmhavebeenwellestab-

lished,thepossibilityforaroleforactininthenucleushas

r,itisnowgenerallyaccepted

swell

asactinbindingproteinshavebeenshowntomediatenu-

er,

actinisfoundaspartofchromatinremodelingcomplexes

andribonucleoproteinparticlesandinteractsdirectlywith

RNApolymerases(159).Actinbindingproteinsandactin

monomersbindtotheAR,indicatingthattheyalsoplayan

mple,

supervillin,anactin-bindingprotein,isabletointeractwith

theARNTDandDBD-LBD(160).Thisassociationisen-

illinincreases

ARtransactivationandcooperateswithotherARcoregula-

tors,er,threedifferent

actinisoformscooperatewithsupervillintostimulatefurther

ARtransactivationinanadditivemanner(161).Conversely,

anactinchelatorthatreducestheavailabilityofmonomer

actinattenuatesthecoactivatorpropertiesofsupervillin

(161).Supervillinhasnoeffectoncytoplasmic-nucleartrans-

locationoftheAR,nordoesitaffectthehalf-lifeoftheAR

(160).Similartotheireffectonsupervillin,androgensin-

creasetheinteractionbetweentheARDBD-LBDandgelso-

lin,anotheractin-bindingprotein,inadose-dependent

ininteractswiththeARduringnuclear

translocationandenhancesligand-dependentARactivity

(162).Inaddition,theF-actincross-linkingproteinfilamin,

whichwasoriginallyidentifiedasaproteinthatfacilitates

nucleartransportoftheAR,interactswiththeARDBD-LBD

r,thisinteraction

enceof

filaminhampersandrogen-inducedARtransactivation(163).

Asecond,smaller90-to100-kDa(insteadofthe280-kDa

form)fragmentoffilamin(termedfilaminA)iscapableof

nucleartranslocationandcolocalizeswiththeARtothe

nucleus(164,165).Thisnaturallyoccurringfilaminfragment

repressesARtransactivationanddisruptsARinterdomain

interactionsaswellashampersSRC-2-activatedARfunction.

Anothercytoskeletalprotein,

␣-actinin-2,enhancesthetrans-

activationactivityofSRC-2andservesasaprimarycoacti-

vatorfortheAR,actinginsynergywithSRC-2toincreaseAR

transactivationfunction(166).␣-Actinin-4alsobindstothe

ARandexhibitscoregulatingproperties(167).Finally,the

actinbindingproteintransgelinsuppressesARfunctionvia

interruptionofAR-ARA54heterodimerization,resultingin

elin

doesnotdirectlyinteractwiththeARbutexertsitseffects

throughrecruitmenttoARA54(168).

Likeactin,microtubulesconstituteaprincipalcomponent

ofthecytoskeletonandhavebeenproposedtoplayanim-

aseofAR-

mediatedtranscription,ARA67/PAT1/APPBP,which

showshomologytokinesinlightchainandbindsmicrotu-

bules,67/PAT1functionsas

uptionofARcytoplasmic-

nuclearshuttlingmayplayamajorroleinARA67/PAT1-

mediatedsuppressionofARactivity(169).

tosismediatesthe

best-characterizedformofendocytosisisthatmediatedby

thebuddingofclathrin-coatedvesiclesfromspecializedre-

in-coatedvesiclesfuse

withendosomes,andthecontentofthevesicleissortedfor

intracellulartransportorrecycledtotheplasmamembrane

(170).Endocytosiscanalsobeachievedinaclathrin-inde-

pendentmannerbyuptakeofmoleculesinsmallinvagina-

tionsoftheplasmamembranetermedcaveolae,whichare

coatedwithcaveolin(171).Interestingly,multipleproteins

involvedinbothmechanismsofendocytosishavebeen

showntointeractwiththeARandtoinfluenceAR-mediated

headaptorproteinsinvolvedinclath-

rin-mediateduptake,huntingtin-interactingprotein1

(HIP1),associateswiththeARandreducestherateofAR

proteindegradation(172).Moreover,HIP1isrecruitedto

pressionofHIP1

sely,transcrip-

HeemersandTindall•FunctionallyDiverseARCoregulatorsEndocrineReviews,December2007,28(7):778–808787

byonJanuary7,nloadedfrom

tionbytheARissignificantlyrepressedafterknockdownof

enstimulationresultsinnuclear

translocationofHIP1,aneventthatreliesonanuclearlo-

calizationsignalattheCOOHterminusofHIP1(172).Re-

markably,anotherendocyticproteintermedAPPL(adapter

proteincontainingPHdomain,PTBdomain,andleucine

zippermotif),thattranslocatestothenucleusupongrowth

factorstimulation,down-regulatesAR-mediatedtranscrip-

ctionbetweenthe

ARandAPPLismediatedbyAkt(173).Inaddition,HAP1

(huntingtin-associatedprotein1),whichfunctionsinendo-

cytosisofmembranereceptorsandendosomaltrafficking,

interactswiththeARthroughitsLBD(174).Thisinteraction

isdependentonthelengthoftheARpolyglutaminestretch

(strongerwithincreasinglength),andtheadditionofan-

G-associatedkinase(GAK),orauxilin2,isanessentialco-

factorforHsp70-dependentuncoatingofclathrin-coatedves-

eractswiththeARNTDandenhancestheAF-1

functionofARactivityinaligand-dependentmanner(175).

Caveolinisaprincipalcomponentofcaveolaemembranes

thatserveasascaffoldproteinofmanysignaltransduction

in-1ligand-dependentlyinteractswiththe

ARNTDandLBD(176).Overexpressionofcaveolin-1sig-

nificantlyincreasesnuclearlocalizationoftheARandpo-

tentiatesligand-dependentARactivation(177).Incontrast,

down-regulationofcaveolin-1expressiondiminishesandro-

gen-inducedAR-mediatedtranscription(176).

Overall,thesefindingssupporttheconceptthatseveral

proteinsinvolvedindifferentaspectsofendocytosisexert

ARcoregulatorycharacteristics.

integratorsandtransducers,scaffolds,

linewiththeARcoregulatorpropertiesofendocyticscaffold

proteinssuchascaveolin-1,severalproteinsinvolvedincell-

cellcontactsandcell-substrateadhesioncomplexesareable

the

casealsoforanumberofproteinsthatfunctionasscaffolds

andadaptorsformultiplesignaltransductionpathways.

AmongtheseareLIN-11,ISL-1,andMEC-3(LIM)domain-

containingproteinsthatcanassociatewithfocaladhesions,

suchasARA55/Hic,paxillinandfour-and-a-half-LIM-only

protein2(FHL2).ARA55bindstotheAR-LBDinaligand-

dependentmannerandreliesonthreeLIMdomainsinits

55enhancestran-

scriptionalactivityoftheAR(178).Interestingly,thefocal

adhesionkinase(FAK)Pyk2isabletorepressARtransac-

tivationbyinteractingwithandphosphorylatingARA55

(179).TheARA55-relatedproteinpaxillinalsolocalizes

withinfocaladhesionsandcanparticipateinanumberof

indirectlyinteractswith

theAR,andoverexpressionofpaxillinresultsinincreased

targetingoftheARtothenuclearmatrix(180).Paxillinfunc-

er,likeARA55,

paxillinreliesonitsCOOH-terminalLIMdomaintointeract

r-and-a-halfLIMdomainproteinFHL2,

whichalsofunctionsatfocaladhesionsaswellasinthe

nucleus,directlyassociateswithfull-lengthARandstimu-

latesAR-mediatedtranscriptioninanagonist-andAF-2-

dependentmanner(181).FHL2hasbeenfoundtointeract

withPELP1/MNAR(proline-,glutamicacid-,andleucine-

richprotein-1/modulatorofnongenomicactionsofthees-

trogenreceptor),whichservesasascaffoldingproteinthat

couplesnuclearreceptorswithvarioussignalingcomplexes

(182).ThePELP/MNARinteractomeharborstranscriptional

regulators,chromatinregulators,splicingfactors,cellcycle

proteins,cytoskeletalregulators,andproteinsinvolvedin

1/MNARinteractswiththeAR

versely,knockdownofPELP1/MNARreducesFHL2-in-

ducedARtransactivation(182).Thus,PELP1functionsasa

molecularadaptor,r

focaladhesionprotein,vinexin

␣,hasbeenidentifiedasa

vinculin-bindingproteinthatplaysakeyroleincellspread-

indstovinexin

␣,andtheligand-inducedtransactivationfunctionoftheAR

isstimulatedbyvinexin␣(183).

Inadditiontofocaladhesioncomponents,severalproteins

involvedinG-coupledreceptorsignalingaffectAR-induced

transcriptionand/GTPase

guaninenucleotideexchangefactor(GEF)Vav3activates

RhofamilyGTPasesbypromotingtheexchangeofGDPfor

3potentiatesARtranscriptionalactivity(184,185).

Incontrast,knockdownofVav3resultsindecreasedAR

reaseinARactivitybyVav3involves

r,Vav3doesnotinteractwiththe

AR,ritsGEFfunction

isrequiredforthestimulationofARtransactivationisstill

underdebate(184,185).Rhoguaninenucleotidedissociation

inhibitor(RhoGDI)wasoriginallyidentifiedasanegative

expressionofRhoGDIincreasesARtranscriptionalactiva-

tion,suggestinganARcoactivator芙蓉镇旅游必去景点 role(186).Physicalinter-

actionbetweenRhoGDIandtheARhasnotbeenassessed.

InterplaybetweenactivatedCdc42-associatedtyrosineki-

1binds

theARandphosphorylatesseveraltyrosineresiduesinits

NTD(187).ActivatedAck1isrecuitedtoAREsandpromotes

inductionofARtargetgeneexpressioninboththepresence

er,knockdownofAck1

decreasesandrogen-stimulatedrecruitmentoftheARto

AREsintargetgenes,suggestingthatAck1isrequiredfor

optimalandrogen-regulatedDNAbindingoftheAR(187).

ProteinkinaseC-relatedkinase(PRK)1/proteinkinaseNis

amemberoftheproteinkinaseC(PKC)superfamilyof

serine/threoninekinasesandisoneofthefirstidentified

nteractswithPRK1

throughtheTAU5domain(188).Blockingofendogenous

PRKsignalingseverelyimpairsagonist-dependentARtrans-

versely,stimulationofthePRKsignalingcascaderesultsin

rmore,

PRK1promotesafunctionalcomplexofARwiththecoac-

tivatorSRC-2(188).RanBPM(Ran-bindingproteininthe

microtubule-organizingcenter)wasoriginallyidentifiedby

interactsdirectlywiththeAR-NTDandDBDinthepresence

ofligandandenhancesandrogen-dependenttranscription

bytheAR(189).RanBPMmayalsoplayaroleinRan-

teworthythatRan/

788EndocrineReviews,December2007,28(7):778–808HeemersandTindall•FunctionallyDiverseARCoregulators

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ARA24interactswiththeARNTDandactsasacoactivator

fortheAR(190),suggestingthatRanBPM,Ran,andtheAR

workinamultiproteincomplex.

Thep21-activatedkinase(PAK6)thatcontainsaputative

amino-terminalCdc42/Racinteractivebindingmotifanda

carboxyl-terminalkinasedomaininteractswitheitherthe

AR-hingeregionorLBD(191–193).IncontrasttomostPAKs,

PAK6activityisnotstimulatedbyCdc42orRac,butcanbe

onsetoandrogens,PAK6

cotranslocatesintothenucleuswiththeARandrepresses

ppressionrequiresitski-

naseactivitybutdoesnotdependuponGTPasebindingto

PAK6andisnotmimickedbythecloselyrelatedPAK1and

PAK6inhibitsnucleartranslocation

ofthestimulatedAR,suggestingapossiblemechanismfor

inhibitionofARresponsiveness(191–193).Interactionwith

PAK6couldprovideamechanismfortheARtocross-talk

ingwith

thisconcept,theadaptor/scaffoldingproteinreceptorfor

activatedCkinase1(RACK1)interactswiththeARthrough

itsLBD(194).RACK1facilitatesligand-independentARnu-

cleartranslocationuponPKCactivationandsuppressesboth

ligand-dependentand-independentARtransactivation

saysrevealadecreaseinAR

recruitmenttoARtargetgenesafterstimulationofPKC.

TheseobservationssupportaroleforRACK1asascaffoldfor

theassociationandmodificationoftheARbyPKC,enabling

translocationoftheARtothenucleusbutrenderingtheAR

unabletoactivatetranscriptionofitstargetgenes(194).An

independentstudyconfirmedtherepressiveeffectofRACK1

onandrogen-dependentgeneexpressionandshowedthat

androgenscanenhancetheassociationbetweenRACK1and

theAR(195).Moreover,RACK1facilitatestheinteraction

betweentheARandSrckinase,whichresultsinincreased

tyrosinephosphorylationoftheAR(195).Itisnoteworthy

thattyrosinephosphorylationbySrcisimportantforAR

nucleartranslocation(196).

Inlinewiththeconceptthatadaptorsformultiplesignal

transductionpathwayscanmodulateAR-driventranscrip-

tion,severaleffectorsofsuchcascadesareabletointeract

withtheARandpositivelyornegativelyalterthetranscrip-

tance,signaltransducerand

activatoroftranscription(STAT)-3canbindtheARand

enhanceARtransactivation(125,197–199).STAT3hasbeen

describedtostimulatethetranscriptionalactivityoftheAR

inahormone-dependentmanneractingsynergisticallywith

SRC-1,P/CAF,CBP,andSRC-2(197).Conversely,DHT-

inducedARactivityisincreasedbyIL-6,acytokineactivat-

ingandsignalingthroughSTAT3(198).Inaddition,associ-

ationoftheARwithSTAT3enhancestheactivityofSTAT3

(199).ARactivationovercomestheinhibitoryeffecton

elieves

STAT3fromSTAT3-PIAS3complexformation(199).Simi-

larly,Smad3,akeycomponentintheTGF␤signalingcas-

cademodulatesAR-mediatedtranscription(200–203).De-

pendingontheexperimentalsettingandthetargetgene

studied,Smad3canactasanARcoactivatororcorepressor.

Protein-proteininteractionbetweenARandSmad3involves

er,ligand-boundARin-

hibitsTGF-␤transcriptionalresponsesthroughselectively

repressingSmad3signaling(203).

Ligand-enhancedbindingofEbp1,anErbB-3bindingpro-

tein,totheARNTDsuggestsalinkalsobetweenErbBre-

ceptorandARsignaling(204).Indeed,ectopicexpressionof

Ebp1inhibitsligand-mediatedtranscriptionalactivationof

ARtargetgenes(204–206).Ebp1participatesinthetran-

scriptionalregulationbytheARviaitsinteractionwiththe

corepressorsHDACandSin3(207).

Supportingthepossibilityforcross-talkbetweenNotch

andandrogen-signalingpathways,Hairy/Enhancerofsplit

relatedwithYRPWmotif1(Hey1),amemberofthebasic

helix-loop-helix-orangefamilyoftranscriptionalrepressors

thatmediateNotchsignaling,interactswiththeARina

ligand-independentmanner(208).Androgen-dependentAR

transcriptionalactivityisinhibitedbyHey1,andexpression

ofaconstitutivelyactiveformofNotchrepressestransacti-

teworthythatHey2,anothermem-

beroftheHeyfamily,isalsoabletorepressARtranscription.

TheinhibitingeffectsofHey1onARtransactivationare

mediatedbyAF-1(208).Similarly,theAR(throughitsLBD)

andtheinterferon-activatedRNaseLinteractinaligand-

dependentmanner(209).Inaddition,overexpressionof

RNaseLinthepresenceofinterferonreducesandrogen-

sely,androgens

areabletointerferewithinductionofgeneexpressionby

interferon,indicatingafunctionalcross-talkbetweenDHT

andinterferonsignaling(209).Finally,theWntsignaling

pathwayalsomodulatesandrogensignalingatmultiplelev-

enspromotethecytoplasmic-nucleartransloca-

tionofbeta-catenin,acriticalcomponentofthissignaling

er,beta-cateninisabletobindtotheAR

LBDinaligand-dependentmanner,isrecruitedtoAREsin

ARtargetgenes,andenhancestranscriptionalactivitybythe

AR(210–214).Furthermore,glycogensynthasekinase-3

␤

(GSK-3␤),aproteinserine/threoninekinasethatregulates

beta-catenindegradation,phosphorylatesandinteractswith

theARandsuppressesitsabilitytoactivatetranscription

(215,216).Incontrast,somereportsmentionaGSK-3␤-me-

diatedincreaseinARtransactivation(217).Furthermore,T

cellfactor4,oneofthetargetsofWntsignalingthatrelieson

beta-cateninfortranscriptionalactivation,interactswiththe

ARDBDandfunctionsasacorepressorfortheAR(214,218).

stingly,severalproteinsin-

volvedintheregulationofcellcycleprogressionalsoasso-

ciatewiththeARandmodulateitstranscriptionalactivity.

Forexample,cyclinEincreasesthetransactivationactivityof

Ebindsdirectlytothe

NTDoftheARandenhancesitsAF-1transactivationfunc-

ctionwiththeARdoesnotrequirecomplexfor-

mationwithCDK2,nordoesitinvolvephosphorylationof

theAR(219).Cdc25Bisacellcycleregulatorthatfunctions

asadual-specificphosphatasetomediatecellcycleprogres-

25Bin-

teractsdirectlywiththeARandstimulatesAR-dependent

transcriptionindependentofitsproteinphosphataseactivity

(220–222).Moreover,P/CAFandCBPinteractandsynergize

withCdc25Bandfurtherenhanceitscoactivationactivity

(220).Furthermore,cyclin-dependentkinase6(CDK6)binds

HeemersandTindall•FunctionallyDiverseARCoregulatorsEndocrineReviews,December2007,28(7):778–808789

byonJanuary7,nloadedfrom

toandisactivatedbycyclinD1andassuchenhancesthe

transitionofcellsthroughtheG

phaseofthecellcycle.

CDK6alsoassociateswiththeARandstimulatesitstran-

fectdoes

notrequireitskinaseactivityandisinhibitedbycyclinD1

andp16INK4a(223).Moreover,CDK6ispresentinassoci-

ationwiththeARatthepromoterregionofARtargetgenes.

Contrarytothecoactivatorpropertiesexhibitedbythesecell

cycleregulators,cyclinD1functionsasacorepressorforthe

AR(224–229).Ligand-mediatedtranscriptionalactivationof

ARtargetgenesisinhibitedbycyclinD1aswellascyclinD3

(224).ThisfunctionofcyclinD1isindependentofitsrolein

D1directlybindstotheARin

D1targetstheAF-1

essoractivityofcyclinD1

canbeexplainedbyitsabilitytorecruitHDACsandits

inhibitionofARN-andC-terminalinteractions(224–229).A

secondisoformofcyclinD1,termedcyclinD1b,iscompro-

misedinitsabilitytoregulateARactivity,althoughitretains

theabilitytoassociatewiththeAR(230).Theretinoblastoma

protein(Rb)functionsasatumorsuppressorbycontrolling

eendescribedto

bindtotheARinanandrogen-independentmannerand

enhancesARtranscriptionalactivityinthepresenceofDHT

(231,232).RbandARA70cooperatewitheachothertoac-

tivatetranscriptionbytheAR(231).Interestingly,pp32,

whichinteractswithRb,alsofunctionsasanARcoactivator

(233).ic-

ingfactorsp54nrbandPSFareadditionalcomponentsofthe

pp32-Rbcomplex(233).Furthermore,Rb-associatedKruppel

protein(RbaK)interactswiththeARLBDinaligand-de-

pendentmanner(234).Finally,apoptosis-antagonizingtran-

scriptionfactor(AATF),alsotermedChe-1,whichhasbeen

showntobindRbandpromotecellcycleprogression,en-

hancesAR-mediatedtransactivationinahormone-and

dose-dependentmannerandactsascooperativecoactivator

forTSG101(115).

tiontoproteinsthatgovern

progressionthroughthecellcycle,afewproteinswithprom-

inentrolesintheexecutionofapoptosisactasARcoregu-

mple,theproapoptoticcaspase-8represses

AR-dependentgeneexpression(236).Itdoesthisbydisrupt-

ingARN/Cinteractionandinhibitingandrogen-induced

rthyisthefactthatcaspase-8

doesnotdependonitsapoptoticproteaseactivitytoexert

e-8interactsdirectlywiththeAR

NTDFXXLFandWXXLFsequences,andmutationsofthese

ARmotifspreventitsrepressiveeffectonAR-mediated

tion,knockdownofcaspase-8byRNA

interferencespecificallyaffectstheandrogen-dependent

expressionofAR-targetinggenes(236).Par-4,anotherpro-

apoptoticprotein,ontheotherhand,actsasanARcoacti-

vator(237).Par-4physicallyinteractswiththeARDBD,is

recruitedtothepromoterofanAR-drivengeneinthepres-

enceofandrogens,enhancesassociationoftheARwith

DNA,en-

inductionofthisgeneiscounteractedbyadominant-nega-

tiveformofpar-4(237).

anpapillomavirus(HPV)E2

oncoproteinhasbeensuggestedtoactasanARcoactivator

byphysicalandfunctionalinteractionswiththeARaswell

astheAR-associatedcoactivatorsSRC-2andZac1(zinc-fin-

gerproteinwhichregulatesapoptosisandcellcyclearrest1).

SRC-2andZac1arebothabletoactsynergisticallywithHPV

E2proteinsonAR-dependenttranscriptionalactivation(238,

239).Similarly,HPVE6andE7areabletointeractdirectly

withtheARintheabsenceandpresenceofandrogens(240).

Dependingonthecelltypeandthepromotercontext,these

oncoproteinsdisplayARcoactivatororcorepressorproper-

stingly,alsothehepatitisBvirusnonstructural

proteinx(HBx)canenhanceARactivity(241,242).HBx

dose-dependentlyincreasesandrogen-stimulatedAR-medi-

snotphysicallyassociatewith

ligand-boundARinthenucleus,anditlikelyaugmentsAR

activitybyincreasingthephosphorylationoftheARthrough

HBx-mediatedactivationofthec-Srckinasesignalingpath-

way(242).

unctionallydiverseproteins

rofproteinsthat

havebeenidentifiedasARcoregulatorscannotbereadily

thesehave

beenreportedtoeitherpositivelyornegativelyregulateli-

nuclearreceptorcoactivatorsthathavebeenshowntoen-

hanceandrogen-dependenttranscriptionbytheARinclude

Asc-1(activatingsignalcointegrator-1)(243),Asc-2(244),

componentsoftheTrap/Mediatorcomplex(63,245),CoCoA

(coiled-coiledcoactivator)(246),NRIP(nuclearreceptorin-

teractionprotein)(247),PNRC(proline-richnuclearreceptor

coregulatoryprotein)(248),TIF-1␣(249),MRF1(modulator

recognitionfactor1)(250),PDIP1(PPAR␥-DBD-interacting

protein1)(251),Zac1(252),GT198(253),andARA70(254).

CorepressorsthatnegativelyaffecttransactivationoftheAR

aswellasothernuclearreceptorscompriseAlien(255),AES

(aminoterminalenhancerofsplit)(256),componentsofthe

SMRTandNCoRrepressorcomplexes(17,257),RIP140(re-

ceptorinteractingprotein140kDa)(258),PATZ(POZ-AT

hook-zincfingerprotein)(259),andTGIF(5TG3interacting

factor)(260).Thisgroupofproteinsalsocontainssomeco-

,ART-27(AR-trappedclone27)(261)and

ARA160(262)],Tip110(263),TZF

(testicularzincfingerprotein)(264–266),andARR19(AR

corepressor19kDa)(267)]thatspecificallyinteractwiththe

egulatorslistedhereinteractwiththeARand

affectitstranscriptionactivityviadifferentregionsofthe

receptor.

velyfewARcoregulators

thesehave

havebeenidentified,including

malegermcell-associatedkinase(MAK).MAKphysically

associateswiththeAR(ARNTD-DBDandDBD-LBDfrag-

ments)(268).MAKandtheARarecorecruitedtopromoters

ofARtargetgenes,andMAKisabletoenhancetheAR

transactivationpotentialinanandrogen-andkinase-depen-

end,MAKactsinsynergywithSRC-3

(268).Inaddition,theSer/ThrproteinkinaseAR-interacting

790EndocrineReviews,December2007,28(7):778–808HeemersandTindall•FunctionallyDiverseARCoregulators

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nuclearproteinkinase(ANPK)interactswiththeDBD-hinge

regionoftheARinaligand-dependentmanner(269).Over-

expressionofANPKenhancesAR-dependenttranscription.

TheARdoesnotappeartobeasubstrateforANPK(269).

Remarkably,alsoDyrk1A,adualspecificitytyrosinephos-

phorykation-regulatedkinasethatshareshomologywith

ANPK,fectof

Dyrk1Aismediatedatleastinpartthroughphysicaland

functionalinteractionwithARIP4,whichisindependentof

itskinaseactivity(270).Similarly,ERK8negativelyregulates

transcriptionalcoactivationoftheARbyARA55inakinase-

independentmanner(271).Theserine/threonineproteinki-

nasep90-kDaribosomalS6kinase(RSK),animportant

downstreameffectorofMAPK,alsoenhancestheexpression

ofARtargetgenes,aneffectthatwasreversedbyinhibiting

parentcoactivatingactivityofRSKin-

volvesbothRSKkinaseactivityanditsabilitytoassociate

withp300(272).

SmallCTDphosphatase(SCP)-2interactswiththeAR

NTD(273).SCP2andtwootherfamilymembers,SCP1and

SCP3,attenuateARtranscriptionalactivityandarerecruited

inanandrogen-andAR-dependentfashionontothepro-

ingofSCP2increases

androgen-dependenttranscriptionandaugmentsARload-

2isinvolved

inpromoterclearanceduringandrogen-activatedtranscrip-

tion(273).Finally,mediatedbytumorantigensimianvirus

40smalltantigen(ST),proteinphosphatase2A(PP2A)can

betransferredontotheligand-activatedAR(274).Transfer

bySTisstrictlydependentontheagonist-activatedconfor-

mationoftheAR,occurswithinminutesoftheadditionof

androgentocells,andcanoccurineitherthecytoplasmor

dlydissociatesfromthecomplexupon

2AistransferredontotheLBD

oftheAR,andthephosphataseactivityisdirectedtofive

phosphoserinesintheNTDAF-1,withacorrespondingre-

ductioninARtransactivation(274).

ainingARcoregulatorsinclude

thetumorsuppressorgenesLATS/2/

KPM,whichpossesseskinaseactivity,interactswiththe

2inhibits

androgen-regulatedgeneexpressionbyamechanismthat

involvestheinhibitionofARN-andC-terminalinteraction.

ChIPassaysrevealedthepresenceofLATS2andtheARat

thepromoterofARtargetgenes(275).PTENalsofunctions

asanARcorepressorviaaphosphatidylinositol-3-OHki-

nase/Akt-independentpathway(276–278).Thedirectinter-

actionbetweentheAR(aminoacids483–651)andPTEN

inhibitsARnucleartranslocationandpromotesARprotein

degradation(278).

Tob1andtheclosely-relatedTob2,membersofananti-

proliferativeproteinfamilyandnegativeregulatorsofos-

teoblastproliferationanddifferentiationbothsuppressAR-

1inhibitsthenuclear

fociformationofDHT-boundAR(279).

ThemultifunctionalDJ-1/PARK7oncoproteinandneu-

romodulatorwasidentifiedasanARcoactivatorbyitsability

tointeractwithPIASx␣/ARIP3andtorestoreARtranscrip-

tionactivitybyabsorbingthecorepressorPIASx␣fromthe

AR-PIASx␣complex(280).DJ-1interactsdirectlywiththe

ARaswell(281).DJ-1-bindingprotein,DJBP,bindstheDBD

oftheARinanandrogen-dependentmannerandcolocalizes

withDJ-1orARinthenucleus(282).DJBPrepressesandro-

gen-dependentARtransactivationactivitybyrecruitinga

-1partiallyrestorestheactivityoftheAR

byabrogatingtheDJBP-HDACcomplex.

Interestingly,apartfromDJ-1,asecondproteinimplicated

inParkinson’sdiseasepossessesARcoregulatoractivity.

Indeed,l-dopa-decarboxylaseinteractswiththeARLBD

andNTDandenhancesARtransactivationactivity(283).

MelanomaantigengeneproteinMAGEA11isanARco-

activatorofparticularinterest(284).Itspecificallybindsthe

ARN-terminalFXXLFmotif,resultinginstabilizationofthe

ligand-freeARand,inthepresenceofanagonist,increases

exposureofAF-2totherecruitmentandactivationbythe

SRC/sactivationincreasesinre-

sponsetoMAGEA11andtheSRC/p160coactivators

throughmechanismsthatincludebutarenotlimitedtothe

,MAGEA11functionsasauniqueARco-

regulatorthatincreasesARactivitybymodulatingtheAR

interdomaininteraction.

SteroidreceptorRNAactivator(SRA)wasoriginallyiso-

latedasacoactivatorforseveralnuclearreceptors,including

theAR,whichactsasanRNAtranscript(285).SRAtran-

scriptsexistindistinctribonucleoproteincomplexesthatcon-

ranslatedaswell,andthreeSRA

isoforms(SRA1–3)enhanceAR-mediatedtranscription

(286).

ictranscriptionfactors

Furtherregulationofthetranscriptionaloutputbythe

ARisachievedbytranscriptionfactorsthatbindtospecific

elastdecade,multiple

transcriptionfactorshavebeenshowntointeractphysi-

callyandfunctionallywiththeAR(287–324)(foranover-

view,seeTable1).RegulationofAR-mediatedtranscrip-

tionbythesefactorsisgovernedbydifferentmechanisms.

DAX-1withtheARLBD(287)]andaffectitsabilityto

interactwithAREswithoutbindingdirectlytoDNAthem-

[e.g.,AP-1(80)]competewiththeARfor

coregulatorsthatarepresentinlimitedsupplywithinthe

atively,,Foxa2

(288)]bindtoDNAsequencesthatareinterspersedbe-

tweenorincloseproximitytoAREs,allowingcooperation

inandcoregulationoftranscriptionofthetargetgenes.

Theimportanceofthislattermechanismofregulatory

cross-talkbetweentheARandmultipleDNA-binding

transcriptionfactorsisunderscoredbytheresultsofsev-

eralrecentChIP-on-chipapproachesaimedatmapping

thegenome-widerecruitmentoftheARandcharacteriz-

ingthelociofARenrichment(325–327).Inthesestudies,

aminorityofthesitesofARoccupancymeetthecriteria

d,mostoftheARbind-

fraction

ngly,thesitesofAR

recruitmentareselectivelyenrichedinbindingmotifsfor

multiplespecifictranscriptionfactorsincludingFoxa1,

HeemersandTindall•FunctionallyDiverseARCoregulatorsEndocrineReviews,December2007,28(7):778–808791

byonJanuary7,nloadedfrom

Oct1,GATA2,ETS1,AP-1,RAR,ZNF42,HNF-4␣,and

EGR(325–327).OccupancyatARbindingsiteshasbeen

confirmedforasubsetofthesetranscriptionfactors(325).

Thepresenceofthesetransactingfactors,insomecases

observedintheabsenceofandrogens,iscriticalforthe

recruitmentoftheARand/orRNApolymeraseII(325).

FullandtimelyandrogeninductionofARtargetgene

expressionrequiresnormalexpressionofthesefactorsand

reliesonthepresenceofintactconsensusbindingmotifs

forthesefactors(325).Moreover,silencingofonetrans-

actingfactorcannegativelyaffectthereciprocaloccu-

pancyoftheARbindingsitesbyanother(325).Overall,

thesestudiesofferafirstglanceatahierarchicalnetwork

oftranscriptionfactorsthatactatandregulatedistinct

stepsinthegenerationoftheARtranscriptionaloutput.

Moreover,theyindicatethatcollaboratingtranscription

factorscanaidtheARinbindingtositesotherthanca-

llaborationcanofferinsightsinto

themannerbywhichtheARisabletoexertfinelytuned

andspatiotemporalregulationoftargetgeneexpressionin

agene-andcell-specificmanner,becausecompositere-

sponseelementsarelikelytofunctionaspointsofregu-

array-basedmethodsaimedat

unravelingtheARinteractomehaveisolatedmoreDNA-

bindingtranscriptionfactorsthatareabletointeractwith

theAR,includingforinstanceAP-2,GATA-3,GATA-4,

andE47(296),suggestingthatthenumberoftransacting

factorsabletosteerARrecruitmentandtranscriptional

challengingbutimportanttocharacterizethemecha-

nism(s)ofcross-talkbetweentheARanditsassociated

transcriptionfactorsatlociofARtranscriptionalactivity

andtoascertainthedistributionandactivityofARco-

regulatorsatthesesites.

ationsandSignificanceoftheConvergence

ofaMultitudeofDiverseFunctionsontheAR

tetranscriptionaloutputbytheARrequiresthe

concertedactionofnumerouscellularpathwaysand

processes

AglanceattheoverviewoftheARcoregulatorsreported

todateandsummarizedinTable2revealsadauntinglevel

offunctionaldiversityamongtheseproteins(seealsoFig.2).

instance,becausetheARtranscriptionalcomplexneedsto

getaccesstothetemplategenomicDNAtoexecutetarget

geneexpressionsuccessfully,itstandstoreasonthattheAR

enliststhehelpofregulatoryproteinsthatcanalleviatethe

ruit-

mentofproteinsthatareabletounwindhigherorderchro-

matinstructuresorloosenDNA-histoneinteractionsisa

ethe(de)acetylasesand

(de)methylasesinvolvedinthislatterprocesscanmodifynot

onlyhistonesbutalsoseveralcomponentsoftheARtran-

scriptionalcomplex,withsevereconsequencesfortheactiv-

itylevelandinterplaybetweentheindividualcomponentsof

thiscomplex,thisallowsforanotherleveloftuningthe

,Refs.63,79,81,84,87,91).The

chromatinenvironmentcanalsobealteredbyubiquitination

andsumoylation(54,55).SeveralARcoregulatorspossess

theenzymaticactivitiesrequiredtoinducethesemodifica-

tionsandaccordinglycanmodifytheARandseveralofits

associatedcofactors,againwithsevereconsequencesforthe

intrinsicactivity,stability,andfunctionalinteractionsof

theseproteinsintheARtranscriptionalcomplex(99–101,

115,120,123).Whethertheseeventscorrespondwithalter-

ationsinthelocalubiquitinationorsumoylationpatternin

thechromatinenvironmentofARtargetgeneshasnotyet

rly,fromamechanisticperspective,

interactionoftheARaswellasseveralofitsassociated

coregulatorswithmultiplecomponentsofthegeneraltran-

rofproteinsthat

arepartofthespliceosomeand/orfunctioninRNAmetab-

olismhavebeenidentifiedascoregulatorsfortheAR.

Traditionally,eventsinvolvedinthematurationof

(pre-)mRNAshavebeendesignatedtobeposttranscrip-

gingview,however,isthatallstepsfrom

transcriptiontotranslationarefunctionallyandmechanis-

ticallycoupledandthatthedifferentstepsofthegeneex-

pressionprocessshouldthereforebeconsideredascotrans-

criptional(138,139).Underliningthelinkagebetweenthe

transcriptionaleventsleadingtotheproductionofaprema-

viewoftranscriptionfactorsthatmodulateAR

activity

Transcription

factor

A/RDirect/indirectRef.

AML3/CBF␣1ADirect289

AP-1RDirect–NTD,LBD80,290,291

ATF2RDirect–DBD292

Brn-1A/RDirect293

c-JunA/RDirect–DBDh,DBD-LBD294,295

c-relRDirect296

c/EBP␣RDirect–NTD,DBDh297

Dax1RDirect–LBD287,298

EGR1ADirect–NTD299

ER␣RDirect–NTD300

FKHRRDirect–NTD,LBD301,302

Foxa1ADirect–DBDh303,304,325

Foxa2A/RDirect–DBD288,304

FoxH1RDirect–NTD-DBD305

GATA-2AND306,325

GATA-3AND306

GRRDirect–DBD307

HoxB13RDirect308

NF1AND309

Oct-1A/RDirect–DBD293,310,325

Oct-2NDDirect–DBD310

Pod-1RDirect–DBDh311

p53RIndirect312,313

PDEFADirect–DBD314

RelARDirect–NTD-DBD315

RXRA/RDirect–LBD316

Sox9A/RDirect–DBD317

Sp1ADirect309,319

SRYRDirect–DBD318

SHPRDirect–NTD,LBD320

SF1ADirect–DBD321

TR2RDirect322

TR4RDirect–NTD,DBD,LBD323

USF2ADirect324

A/R,Transcriptionfactoractivates(A)orrepresses(R)ARfunction;

direct/indirect,thetranscriptionfactorinteractsdirectlyorindirectly

withtheAR;ND,notdetermined;DBDh,DBD-hinge.

792EndocrineReviews,December2007,28(7):778–808HeemersandTindall•FunctionallyDiverseARCoregulators

byonJanuary7,nloadedfrom

ewofARcoregulatorsidentifiedtodate

CoregulatorcoA/coRDirect/indirectRef.

entsofthechromatinremodelingcomplex

ARIP4coA–defDirect56,57

BRG1coA–defND–ChIP58,63

hBRMcoA–defND58

BAF57coA–DNDirect–ChIP,CoIP59

SRG3/BAF155coA–overDirect–ChIP,CoIP60

SRCAPcoAND61

hOsa1/BAF250coAND62

hOsa2coAND62

emodifiers:acetyltransferasesanddeacetylases

SRC-1coADirect–ChIP53,63,70,72–75

SRC-2coADirect–ChIP,CoIP64,69–73,75,213

SRC-3coA–overDirect–ChIP63,73,75,76,337

p300coA–siDirectandindirect–ChIP78,79–81,337

CBPcoADirectandindirect–ChIP64,78,80

P/CAFcoADirectandindirect78–81

Tip60coADirect–ChIP82–84

HBO1coRDirect85

SIRT1coRDirect–CoIP87

HDAC7coRDirect88

HDACs,severalcoR–siIndirect–ChIP,CoIP17,63,82–84

emodifiers:methyltransferasesanddemethylases

CARM1/PRMT5coA–siIndirect–ChIP89–91

PRMT1coA–overIndirect92

G9acoA–siIndirect–ChIP93

NSD1/ARA267␣coADirect94,95

LSD1coA–siDirect–ChIP65,67

JHDM2AcoA–siDirect–ChIP66

JMJD2CcoA–siDirect–ChIP,CoIP67

entsoftheubiquitination/proteasomepathway

E6-APcoA–def,overDirect–ChIP98

Mdm2coR–overDirect–ChIP,CoIP99,100

PIRH2coA–siDirect–ChIP,CoIP101

SNURF/RNF4coADirect102–104

ChipcoRDirect105–107

ARNIPNDDirect108

ARA54coADirect109

MKRN1coRND111

USP10coADirect112

UBCH7coAND113

TSG101coA/coRND114,115

entsofthesumoylationpathway

SUMO-1coRND120,121

SUMO-2coAND121

SUMO-3coADirect121

Ubc9coADirect122,123

PIAS1coA/coRDirect126–128,130,131

PIAS3coA/coRDirect124,127,128,131

PIASx␣/ARIP3coA/coRDirect127,130,131

PIASx␤coA/coRDirect127,128,131

PIASycoRDirect132

Zimp7coAND134,135

Zimp10coADirect133,135

SENP1coA–si,overIndirect136

Uba3coRND137

nsinvolvedinsplicingandRNAmetabolism

PSFNDDirect–MS140

PSP1NDDirect–MS140

PSP2NDDirect–MS140

p54nrbcoADirect–MS140

p102U5snRNP/ANT-1coADirect141,142

hnRNPA1coR–si,overIndirect143

p44/MEP50coA–defDirect–ChIP91

nsinvolvedinDNArepair

Ku70coADirect–ChIP,CoIP,MS144

Ku80coA–siDirect–ChIP,CoIP,MS144

DNA-PKccoAIndirect–MS144

Rad9coR–overDirect–CoIP145

BRCA1coA–overDirect146,147

BRCA2coADirect148

(Continued)

HeemersandTindall•FunctionallyDiverseARCoregulatorsEndocrineReviews,December2007,28(7):778–808793

byonJanuary7,nloadedfrom

ued

CoregulatorcoA/coRDirect/indirectRef.

onesandcochaperones

Hsp40coADirect14,149,150

Hsp90coADirect–MS14,167

Hsp70coADirect–MS,ChIP14,167,156

DjA1coR–defIndirect151

Cdc37coAIndirect152

FKBP52coA–defIndirect153,154

FKBP51coA–overIndirect–CoIP154,155

Bag-1LcoADirect–ChIP,CoIP156,157

eletalproteins

ActincoAND161

SupervillincoADirect160,167

GelsolincoADirect–MS162,167

FilamincoADirect–CoIP,MS163

Filamin-AcoRND,direct–CoIP164,165

␣-actinin-2coAIndirect166

␣-actinin-4coA/coR–siND–MS167

TransgelincoR–si,overIndirect168

ARA67/PAT1/APPBPcoR–overDirect169

nsinvolvedinendocytosis

HIP1coA–siND–ChIP172

APPLcoR–overIndirect173

GAK/auxillin2coADirect–CoIP175

Caveolin-1coADirect–CoIP176,177

integratorsandtransducers,scaffoldsandadaptors

ARA55coA–si,DNDirect–ChIP178

PaxillincoADirect180

FHL2coADirect181

PELP1/MNARcoADirect–CoIP,MS182,167

Vinexin-␣coADirect183

Vav3coA–si,overIndirect184,185

RhoGDIcoAND186

Ack1coA–si,overDirect–ChIP187

PRK1coADirect–ChIP188

RanBPMcoADirect–CoIP189

ARA24/RancoADirect190

PAK6coRDirect191–193

RACK1coR–siDirect–CoIP194,195

STAT3coADirect–CoIP125,197–199

Smad3coA/coR–overDirect–CoIP200–203

Ebp1coR–siDirect–ChIP,CoIP204–207

Hey1coRND–CoIP208

Hey2coRND208

RNaseLcoRDirect–CoIP209

␤-catenincoA–siDirect–ChIP,CoIP210–214

GSK-3␤coA/coRDirect215–217

TCF4coRDirect–CoIP218

cleregulators

CyclinEcoA–overDirect219

cdc25BcoADirect220–222

CDK6coA–overDirect–ChIP223

CyclinD1coR–overDirect–CoIP224–229

RbcoADirect231,232

pp32coAND–CoIP233

RbaKcoADirect234

AATF/Che-1coAND115

torsofapoptosis

Caspase8coR–siDirect–CoIP236

Par-4coA–DNDirect–ChIP237

ncoproteins

E2coADirect238,239

E6coA/coRDirect240

E7coA/coRDirect240

HbxcoAIndirect241,242

unctionallydiverseproteins

Nuclearreceptorcoregulators

Asc-1coADirect243

Asc-2coAIndirect–ChIP244

Trap/MediatorcomplexproteinscoA–siDirect–ChIP,CoIP63,245

794EndocrineReviews,December2007,28(7):778–808HeemersandTindall•FunctionallyDiverseARCoregulators

byonJanuary7,nloadedfrom

turemRNAanditssubsequentprocessing,splicingfactors

interactnotonlywiththeARbutalsowithRNApolymerase

IIsubunits(138).Moreover,thenuclearcompartmentsspe-

cificallyenrichedinsplicingfactorsseemtobeincloseprox-

imityofandpotentiallyoverlapwiththosewhereactive

transcriptionistakingplace(138).Similarly,couplingbe-

tweentranscriptionandDNArepairallowsfortheremoval

andrepairofobstaclesandDNAlesions(329–331).Thus,AR

coregulators,whichalsofunctioninDNArepairmecha-

nisms,

noteworthythattranscription-DNArepairlinkagetypically

involveschromatinremodelingactivityaswellastheaction

oftheubiquitin/proteasomepathway.

SomeofthefunctionsassignedtoAR-associatedcoregu-

latorsmay,atleastatfirstsight,behardertoreconcilewith

ample,theidentificationofseveralARcoregulatoryproteins

withanactiveroleinendocytosis,aprocessthatoriginates

attheplasmamembraneandtakesplacepredominantlyin

thecytosol,portanttokeep

inmind,however,thatendocyticproteinsareintrinsically

connectedwiththeactincytoskeletonandfunctionasscaf-

foldsthatareabletolinkseveralfunctionallyrelatedoreven

ussedabove,

componentsofthe(actin)cytoskeletonaswellastransducers

andeffectorsofmultipleintracellularsignalingpathways

er,at

leastforsomeendocyticproteins,includingHIP1,fractions

oftheircellularpoolareabletoundergonucleocytoplasmic

alfofthecellularHIP1translocatestothe

nucleusinanandrogen-dependentmannerwhereitisre-

cruitedtoAREs,directlylinkingtheendosomalcompart-

mentandtheARtranscriptionalcomplex(172).Finally,itis

reasonabletoconsiderthattheendocyticcompartmentin

AR-mediatedtranscriptionisrelatedtoreceptor-mediated

ncepthasbeenproposedforsomenuclear

ued

CoregulatorcoA/coRDirect/indirectRef.

CoCoAcoAIndirect246

NRIPcoA–siDirect247

PNRCcoADirect248

TIF1-␣coA–siIndirect249

MRF1coADirect250

PDIP1coAND251

Zac1coAIndirect252

GT198coADirect253

ARA70coA–DNDirect235,254

AliencoR–overDirect–ChIP,CoIP255

AEScoRDirect256

SMRTcoR–siDirectandindirect–ChIP,CoIP17

NCoRcoR–siDirectandindirect–ChIP17,257

RIP140coRDirect–ChIP258

PATZcoR–ASIndirect259

TGIFcoRDirect260

ART-27coADirect261

ARA160coADirect262

TIP110coR–overDirect263

TZFcoRDirect264–266

ARR19coRDirect267

Kinasesandphosphatases

MAKcoA–si,DNDirect–ChIP,CoIP268

ANPKcoADirect269

Dyrk1AcoAIndirect270

ERK8coRIndirect271

RSKcoAIndirect272

SCP2coR–siDirect273

PP2AcoRDirect274

Diversefunctions

LATS2/KPMcoR–overDirect–ChIP275

PTENcoR–def,overDirect–CoIP276–278

Tob1coRND279

Tob2coRND279

DJ-1/PARK7coADirectandindirect–CoIP280,281

DJBPcoRDirect282

L-dopa-decarboxylasecoADirect283

MAGEA11coADirect284

SRAcoAND–CoIP285,286

coA,Coactivator;coR,corepressor;direct/indirect,directorindirectassociationwiththeAR;ND,secoregulatorsfor

whichinteractionbetweenendogenouslyexpressedcoregulatorandARhasbeendescribed,themethodbywhichthisinformationwasobtained

isnotedasCoIP(coimmunoprecipitation),MS(massspectrometry)rly,coregulatorsforwhichthefunctionhasbeenconfirmed

byassessingtheexpressionofARtargetgeneshavebeenmarkedassi(confirmationoffunctiononendogenouslyexpressedARtargetgenes

obtainedbysiRNA-mediatedknockdownofcoregulatorexpression),AS(confirmationobtainedviaantisenseoligos),DN(verificationof

coregulatorfunctionbydominant-negativeisoforms),def(coregulator-deficientcellswereusedtoverifyfunction),orover(overexpression

experimentswereperformed).

HeemersandTindall•FunctionallyDiverseARCoregulatorsEndocrineReviews,December2007,28(7):778–808795

byonJanuary7,nloadedfrom

receptors,includingtheAR(332).Thestructuralassociation

ofthecytoskeletonaswellasscaffoldproteinsandsignal

transducerswithendosomesdoesnotprecludearolefor

theseelementsinAR-mediatedtranscriptionthatisinde-

ortanceofthecytoskeleton

inARtransactivationseemstoberelatedmainlytothesuc-

cessfultranslocationoftheARtothenucleus,althoughboth

actinandactin-bindingproteinsarepresentinthenuclear

rly,theimportanceof

chaperoneandcochaperonesinAR-governedtranscription

isnotmerelyrelatedtotheirroleinassuringtheproper

foldingthatenablestheARtobinditsligand—aneventthat

tion,

(co)chaperonesareneededtoensuretheconformationofthe

ligand-boundARthatallowsitsnuclearentry(14).More-

over,severaloftheseproteinshavebeenfoundtocomplex

withtheARwithinthechromatinenvironmentoftarget

genes(156).Noteworthyisthefactthatchaperonesalsofulfill

importantfunctionsinthecoatingand/oruncoatingofen-

studiesconfirmtheinteractionoftheAR

withmultiplecomponentsofthecellularpathwayssumma-

rizedhere(167).Itshouldbenotedalsothattheclassification

weputforwarddoesnotprecludeadditionalrolesforAR-

interactingregulatoryproteinsinthetranscriptionalprocess,

suchasanarchitecturalfunctionintheassemblyofnucleo-

proteinstructuresashasbeenproposedforSNURF/RNF4

(333).

lyoftheARtranscriptionalcomplex

TheisolationofamultitudeofproteinswithARcoregu-

latorypropertiesleadstospeculationaboutthemannerin

whichtheformationoftheARtranscriptionalcomplexis

theworkaimedatresolvingthisissue

hasbeendoneusingthegeneencodingprostatespecific

antigen(PSA)ecaseformost

otherARtargetgenesidentifiedtodate,androgenregulation

ofthePSAgeneinvolvesenhancerandpromoterelements.

DuetothepresenceofAREs(AREIandIIinthepromoter

region,AREIIIintheenhancerregion),thePSAenhancer

andpromoterregioneachdisplayandrogenresponsiveness,

butmaximalandrogenregulationrequirestheinvolvement

ofbothregions(334,335).Thusfar,aratherlimitedsetof

coregulatorshasbeenevaluatedintheformationoftheAR

transcriptionalcomplexatthePSAgene(64,336–338).This

groupconsistsmainlyofregulatoryproteinsthatarecom-

mon,corecomponentsofthetranscriptionalcomplexes

formedbymanynuclearreceptorsandspecifictranscription

factors,suchasSRC-1,SRC-2,SRC-3,p300,P/CAF,BRG1,

drogenstimulation,theAR

isrecruitedtoboththeenhancerandthepromoterofthePSA

gene,followedbytherecruitmentofthesecoactivatorsand

rytoRNApolymeraseII,which

displaysanoverallhigheroccupancyatthepromoterregion,

therelativeabundanceoftheARanditsassociatedcoacti-

emod,Chromatinremodeling;HMT,histone

methyltransferase;HDM,histonedemethylase;UB,componentsoftheubiquitination/proteasomepathway;SUMO,componentsofthesumoy-

lationpathway.

796EndocrineReviews,December2007,28(7):778–808HeemersandTindall•FunctionallyDiverseARCoregulators

byonJanuary7,nloadedfrom

oactivators

studied,CARM-1istheonlyexception,beingrecruitedsolely

l,acombinatorialratherthan

asequentialrecruitmentofcoactivatorsappearstobein-

volved,withmembersofthep160familyofcoactivators

elsofproteinsboundatthe

regulatoryregionsofthePSAgenerisegradually,reaching

amaximumat16hafterstimulationandthenslowlyde-

eticsofARcoactivatorbindingtothePSA

regulatoryregionscorrelatewellwiththoseofPSAgene

transcription(337).Elegantmolecularapproacheshaveledto

theproposalofanintegratedchromosomallooping/RNA

polymeraseIItrackingmodelresultingfromtheenhancer-

model,therecruitmentofAR

anditscoactivatorsatboththeenhancerandpromoterre-

gionscreatesachromosomalloopthatallowsenhancer-

boundARandpromoter-boundARtoshareacommonco-

ametime,itpermitsRNA

polymeraseIItotrackfromtheenhanceralongthelooped

chromatintothepromoterregion(337).

AsindicatedinTable2,thepresenceofseveralotherAR

coregulatorsatregulatoryregionsofthePSAgenehasbeen

ethesestudieshavefocusedprimarilyon

therecruitmentofasinglecoregulatortoaparticular

genomicARbindingsite,theydonotprovidefurtherinfor-

mationregardingtheoverallassemblyoftheARtranscrip-

tionalcomplex,thedynamicsofitsformation,ortherelative

importanceofrecruitmenttotheenhancerandthepromoter.

Resolvingtheseissueswillrequireconcertedeffortsofmul-

rly,itwill

bevitaltoassesswhetherthemannerinwhichtheARco-

regulatorcomplexisassembledatthePSAgenecanbegen-

respect,theforma-

tionoftheARtranscriptionalcomplexattheKLK2gene,a

ARtargetgenewithanenhancer/promoterorganization

thatissimilartothatofthePSAgene,appearstoprogress

alongthesamelines(64).Veryrecently,severalsystemap-

proachstudiesaimedatevaluatingthegenome-widebind-

ingoftheARsuggestthatmany,ifnotmost,ofthetarget

genesidentifieddifferconsiderablyintheirgenomicorga-

nizationandinthelocalization,composition,andclustering

ofAREsgoverningandrogen-regulatedtranscriptionof

thesegenes(325–327).Follow-upstudieswillthereforebe

criticaltoaddressingthemannerinwhichARcoregulators

y,theimpact

ofcelltype-specificcontextontheseeventswillneedtobe

explored.

odationofcoregulatorsbytheAR

Anintriguingquestionrelatestothemannerinwhichthe

ARcanaccommodatephysicalinteractionwithsuchaper-

ghsomeoftheseregu-

latorsarerecruitedtotheARtranscriptionalcomplex

throughanintermediaryprotein,themajorityofthemseem

tobeabletoassociatedirectlywiththeAR(Table2).Inter-

actionofcoregulatorswithdifferentregionsoftheARmay

rmeanstowardreducingthecom-

plexityoftheAR-cofactorinteractioncouldlayinthetem-

poralrecruitmentandreleaseofcoregulatorstoandfromthe

teinsightsintothesematterswillrequire

concertedandextensiveChIPandRe-ChIPapproachesand

willmostlikelydependoncollaborativeeffortsfromseveral

researchgroupsworkinginthisfield.

SomeAR-西宫秋怨王昌龄 associatedcoregulatorshavebeenclaimedto

cases,theseobserva-

tionswereperformedatthetimeofisolationoftheprotein

inquestion,withfurthercharacterizationindicatinga

mple,

ARA70,thefirstARcoactivatortobeidentifiedbyayeast

two-hybridapproach,wasinitiallyputforwardasanAR-

specificcoregulator,buthassincebeenshowntomodulate

transcriptionbyseveralothernuclearreceptors(254,339).

FHL2,ontheotherhand,doesdisplayspecificityfortheAR

whencomparedwithothernuclearreceptorsbutisknown

toactalsoasacofactorforseveralspecifictranscription

factors(340).Therefore,thenumberoftrulyAR-specificco-

ntheinformation

availabletodate,ART-27andARR19appeartheonlyco-

regulatorsthatcanbequalifiedasAR-specific.

Ontheotherhand,coregulatorshavebeenshowntodis-

playselectivityintheparticularsetofARtargetgeneswith

whichtheyassociate(58,341).Detailedexplorationofthis

patternofselectivitymayrequireChIP-on-chipapproaches.

Moreover,thetissueandcelltype-selectiveexpressionpat-

ternobservedforsomecoregulatorsandandrogen-regulated

changesintheexpressionofARcoactivators(341–344)may

allowfurthermodificationofAR-coregulatorassociation.

Alongthesamelines,evidenceforagonist-orantagonist-

mediatedinductionofchangesintheposttranslationalmod-

ificationstatusofAR-associatedcoregulatorymachineryis

startingtoemerge(257,345).Suchchangesmaypredispose

coregulatorstointeractselectivelywithparticularregulatory

componentsoftheARtranscriptionalcomplexorleadtothe

releaseofcofactorsfromthiscomplex.

gulatorsin(Patho)Physiology

ThedependencyoftheARonitscoregulatorstoforma

productivetranscriptionalcomplexsuggestsanimportant

rolefortheseregulatoryproteinsinthedevelopmentand

maintenanceofandrogen-responsivetissuesaswellasin

keepingwiththisnotion,someAR-associatedcoregulators

displayselectiveorenrichedexpressioninandrogen-depen-

rlevelof

selectivitycanbeachievedbyrestrictingtheexpressionto

tance,FHL2isselectivelyenriched

inepithelialcellsoftheprostate,whereasARA55/Hic-5is

preferentiallyexpressedintheprostaticstromalcompart-

ment(181,346).Moreover,tissue-selectiveARcoregulator

splicevariantshavebeendescribed,and,interestingly,such

alternativespliceformscanexhibitachangeinactivityfrom

corepressortocoactivatororviceversa(266).Theideathat

androgen-responsivetissuesrelyonAR-coactivatorexpres-

sionfortheirfunctionalandstructuralintegrityissupported

coregulator-deficient

micedemonstrateembryoniclethality,whichsuggestsan

importantroleearlyindevelopmentand/oranactivitythat

HeemersandTindall•FunctionallyDiverseARCoregulatorsEndocrineReviews,December2007,28(7):778–808797

byonJanuary7,nloadedfrom

iscriticalforoverallphysiology(347).Incontrast,othermod-

elsappeartobephenotypicallynormal,suggestingthatthe

functionofthecoregulatorthatisbeingtargetedmayoverlap

withandberescuedbytheactionofothercofactors(347).The

actualinvolvementoftheARinthesephenotypes,however,

othercoregulators,suchasthose

listedinTable3(98,153,154,348–351),givesrisetohormone-

resistantphenotypeswithvaryingdegreesofseverityrang-

ingfromcompromisedfertilitytohypospadiasandchanges

inthecompositionofprostate,seminalvesicles,andtestis.

Interestingly,AR-associatedcoregulatorshavebeen

showntobeimportantforthedevelopmentofpathologies

tecancer(PCa)

lsdepend

onandrogensforproliferation,acharacteristicthatisbeing

-calledandrogen

ablationtherapyeithertargetstheproductionofandrogens

orinterfereswiththeactivityoftheAR(352).Although

androgenablationtherapyisinitiallysuccessfulinthema-

jorityofcases,eventuallymosttumorswillfindawayto

circumventthisformoftreatmentandemergeasandrogen

depletion-independent(ADI)cancers(353).Remarkably,de-

spitethecastratelevelsofcirculatingandrogensinthese

patients,theARisstillacriticaldeterminantforADIPCacell

proliferation(3,354,355).Theunexpected“reactivation”of

theARinADIPCacellshasbeenattributedtomechanisms

ofARhypersensitivity(ARamplificationand/ormutations),

promiscuousactivationoftheAR(byadrenalandrogens,

nonandrogenicsteroids,andevenantiandrogens),outlaw

ARpathways(ARactivatedbygrowthfactorsandcytokines,

therebybypassingtheneedforandrogens),andlocalintra-

crineproductionofandrogens(independentofthelowcir-

culatingserumandrogenslevels)(356,357).Overthelastfew

years,theimportanceoftheinvolvementofARcoactivator

proteinsinADIARactivationisincreasinglybeingrecog-

nized(358).IntheprogressionofPCa,asubsetofARcoac-

lated

expressionofARcoactivatorstendstoincreasewithtumor

dedifferentiationandtocorrelatewithaggressivedisease

er,overexpressionofthesereg-

ulatoryfactorshasbeendemonstratedtocontributesubstan-

tiallytotheADImechanismsofARactivationdescribed

ore,overexpressionofARcoactivatorsiscon-

sideredtobeavaluabletargetfortherapeuticintervention

(358).Themolecularmachineryunderlyingtheaberrantex-

pressionofthesecriticalcofactorsinPCadiseaseprogression

isunderintenseinvestigationasapotentialtherapeutictar-

getforthetreatmentofthisseveredisease(343,344).Simi-

larly,effortsarebeingdirectedtowarddefiningthoseregions

withintheARthatcanmediatecriticalinteractionswith

workfromourlabora-

toryledtotheisolationofadiscreteWXXLFmotifintheAR

NTDthatisessentialforligand-independentARactivitythat

isresistanttoantiandrogenssuchasbicalutamide(359,360).

InadditiontoPCa,atleastonecaseofcompleteandrogen

insensitivitysyndrome,whichistypicallylinkedtoanin-

activatingmutationoftheAR(1,2),hasbeensuggestedto

becausallyrelatedtoadefectinoranabsenceofanAR-

interactingregulatoryprotein,ratherthantoanaberrationof

thereceptoritself(361).Veryrecently,anintriguinginterplay

betweenHBx,anonstructuralhepatitisBvirusproteinacting

asacoactivatorfortheAR,andtheARofhosthepatocytes

hasbeenproposedtounderlythemalepredominanceof

hepatocellularcarcinoma(242).Becauseotherviraloncop-

roteinshavebeensuggestedtobeabletoregulatethetran-

scriptionalactivityoftheAR(239,240),andbecausemales

areknowntobemorevulnerabletomicrobialinfections,this

y,co-

activatorsoftheARmayalsoplayaroleinrelativelymild

conditionssuchasandrogenicalopecia(362).

sionsandFutureDirections

Asillustratedbythisoverview,amultitudeofcoregula-

torswithdiversefunctionshavethepotentialtoconvergeon

der-

ablepartofthisinformationhasbeenderivedfrominvitro

studiesandtheuseofpromoter-reporterconstructsthatmay

notfullyrecapitulatetheactivityoftheARinachromatin

,therefore,bevitaltomonitorthecon-

structionoftheARtranscriptionalcomplexandthetran-

scriptionaloutputitgeneratesinmodelsystemsthatexpress

udieswillalsohelptodetermine

theimportanceoftissueselectivityintherecruitmentof

coregulatorstotheARandtheselectiveinvolvementofpar-

ticularcellularpathwaysintheseevents.

Althoughanimpressivenumberofdifferentfunctions

havealreadybeenascribedtotheregulatoryproteinsin-

volvedintheformationofaproductiveARtranscriptional

complex,additionalpropertiesallowingtheseproteinsto

modulatetransactivationbytheARcannotberuledout.

Typically,investigationintothefunctionalinteractionsbe-

tweentheARanditscoregulatorsremainslimitedtothe

ay,however,

haveareciprocaleffectontheintrinsicactivityofitscoregu-

ssibilityissupportedbytheobservationthat

theAR,independentlyofitsDNAbindingability,dramat-

icallyincreasestheintrinsictranscriptionalactivityofSRC-2,

CBP,andp300thataretetheredtoDNA(363).Thiskindof

ionofcoregulator-deficientmousemodelsshowingvaryingdegreesofandrogenresistance

CoregulatortargetedPhenotypeRef.

BRM/Slightlyreducedtestisweight348

E6-AP/Reducedtestisweight,reducedfertility,defectsinspermproductionandfunction,

attenuatedgrowthanddevelopmentoftheprostategland

98,349

FKBP52/Mildtoseverehypospadias,ambiguousexternalgenitalia,malformationoftheseminalvesicles,

reductionofanteriorprostate,milddysgenesisofdorsolateralandventralprostate

153,154

SRC-1/Reducedtestisweight,decreasedgrowthanddevelopmentoftheprostate350

SRC-2/Hypofertility,defectsinspermiogenesis,testiculardegeneration351

798EndocrineReviews,December2007,28(7):778–808HeemersandTindall•FunctionallyDiverseARCoregulators

byonJanuary7,nloadedfrom

“triggering”phenomenonmightalsobeimportantinthe

nongenomicactionsoftheAR(whichhavenotbeenad-

dressedinthecurrentmanuscript).Moreover,mounting

evidencesuggeststhattheARfeedsbacktoregulatethe

compositionandactivityofitscoregulatorcomplexby

modulatingtheexpressionofitscofactors(341–344).Simi-

larly,ithasbeensuggestedthatcoactivatorssuchasSRC-3

undergoposttranslationalmodificationsuponandrogen

treatment,resultinginspecificmodification“codes”that

governpreferencesinitsinteractionwithotherregulatory

proteins(345).

Anemergingviewisthatcoregulatorsalsofunctionas

signalintegrators,relayinginformationfromthecellsurface

tothenucleus(328).Itwillbeimportanttodetermine

whetherthisholdstruealsofortheARandtoidentifythe

signalingmechanismsinvolved.

Acknowledgments

Weapologizetoauthorswhoseworkwasinadvertentlyoverlooked

orcouldnotbecitedduetospaceconstraints.

Addressallcorrespondenceandrequestsforreprintsto:

l,DepartmentsofUrologyResearch/BiochemistryandMolec-

ularBiology,MayoClinic,2001stStreetSW,Rochester,Minnesota

55905.E-mail:@

ThisworkwassupportedbyNationalInstitutesofHealthGrants

CA121277,CA91956,CA15083,CA125747,andDK65236andtheT.J.

MartellFoundation.

DisclosureSummary:ts

forGlaxoSmithKline,Inc.,andreceivedlecturefeesfromGTx,Inc.,and

TakedaPharmaCo.

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