Transcriptional Coregulator RIP140: an Essential Regulator of Physiology

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j nautiyal RIP140 in reproduction, 58: 3 R147–R158 Review metabolism and cancer

Transcriptional coregulator RIP140: an essential regulator of physiology

Jaya Nautiyal Correspondence should be addressed Institute of Reproductive and Developmental Biology, Faculty of Medicine, Imperial College London, to J Nautiyal London, UK Email [email protected]

Abstract

Transcriptional coregulators drive gene regulatory decisions in the transcriptional Key Words space. Although transcription factors including all nuclear receptors provide a docking ff coregulators platform for coregulators to bind, these proteins bring enzymatic capabilities to the gene ff RIP140 regulatory sites. RIP140 is a transcriptional coregulator essential for several physiological ff cancer processes, and aberrations in its function may lead to diseased states. Unlike several ff metabolism other coregulators that are known either for their coactivating or corepressing roles, in ff obesity gene regulation, RIP140 is capable of acting both as a coactivator and a corepressor. The ff adipose role of RIP140 in female reproductive axis and recent findings of its role in carcinogenesis ff mammary gland and adipose biology have been summarised. ff ovulation ff inflammation

Journal of Molecular Endocrinology

Journal of Molecular Endocrinology (2017) 58, R147–R158

Introduction

We have come a long way in the understanding by acting as scaffolds and in several cases also possess of transcriptional coregulators from when they enzymatic activities to activate (as coactivators) or inhibit were first identified as transcription factor-binding (as corepressors) gene expression. In fact, recent findings proteins (Glass et al. 1990, Bastian & Nordeen 1991, suggest that these proteins perform functions beyond Chatterjee et al. 1991, Wieland et al. 1991, Cavailles et al. nucleus in the cytoplasm to regulate several biological 1994, Halachmi et al. 1994, Onate et al. 1995) to now functions. Coregulators are secondary transcription when they are recognised as key players in influencing factors that are brought to the site of transcription all physiological processes (Lonard & O’Malley 2007, by transcription factors but do not bind to the DNA O’Malley et al. 2008, York & O’Malley 2010, Nautiyal et al. directly. However, these are the factors that control 2013a, Dasgupta et al. 2014, Stashi et al. 2014). These gene expression by bringing enzymatic potentials to the proteins are essential for gene regulation, by regulating gene regulatory sites. Numerous studies using transgenic functions of transcription factors including all members technologies in mice and cell-based assays have revealed of the nuclear receptor superfamily in the genome. the powerful potential these proteins possess in regulating Coregulators (a class of molecules that include both normal physiology and driving diseased states. Today transcriptional coactivators and corepressors) function by 350+ proteins are known as coregulators and the number bringing together multi-partner transcriptional machinery keeps increasing (Millard et al. 2013, Stashi et al. 2014).

10.1530/JME-16-0156 Journal of Molecular Endocrinology As weknowittoday, RIP140isacoregulatortomost effect ER-mediated transcription ( the ligandoestrogen(E2)andantagonists(Tamoxifen) to whose bindingwasselectivelyregulatedorinhibitedby a gapintheunderstandingofbindingpartnersER cells withoestrogenoranti-oestrogens.Thus,therewas and thisbindingwasnotaffectedbytreatmentofthe known tobindER( (TBP) andTBP-associatedfactor(TAF), hTAFII30, was machinery, composed of the TATA box-binding protein 1994 domain ofoestrogenreceptor to identifyinteractingpartnersofthehormone-binding was firstidentifiedinhumanbreastcancercellsascreen functions bothasacoactivatorandcorepressor( RIP140, however, isauniquelyreportedcoregulatorthat for retinoid and thyroid hormone receptors (SMRT)). receptor corepressors-1(NCoR1)andsilencingmediator (PGC-1) families)orcorepressors(examples,nuclear proliferator-activated receptorsgamma(PPAR of steroid receptor coactivator (SRC) and peroxisome Coregulators areeithercoactivators(examples,members a switch coregulator Receptor-interacting protein140 (RIP140): its roleincarcinogenesis hasbeendiscussed. reproductive tissues,adipose,andcurrentknowledgeon physiological functions.RIP140functionsinfemale RIP140, acoregulatorthatperformsseveralimportant This articleelaboratesonthebiologicalfunctionsof DOI: 10.1530/JME-16-0156 http://jme.endocrinology-journals.org Review , 1995 ). Atthisstage,onlythebasaltranscriptional Brou t al et . 1993 j α

). ), . LXXLL motifs( of proteins have 3 LXXLL motifs, whereas RIP140 has 9 their respectiveinteractomes.Forexample,SRCfamily sequences ondifferentcoregulators,whichdetermines However, thereis variation inthenumber of LXXLL are commontoseveraltranscriptionalcoregulators. acid) ( sequence motif(whereLisleucineandXanyamino andcoworkers,isashortalphahelical identified byHeery motifs and transcriptionfactorsarebroughtaboutby ( and retinoicXreceptor(RXR)( required forinteractionwithretinoicacidreceptor(RAR) the C-terminusonRIP140protein.TheLXXMLmotifis to 9LXXLLmotifsand a 10thLXXML motif mapped to ( nuclear receptorsandseveralothertranscription factors RIP140 to act as a coactivator ( and cellshave testified tothisremarkableability of with otherfactors.Severalstudiesinphysiologicalmodels coactivator andcorepressorbasedoninteractiondynamics of atruncationinPit-1.Thus,RIP140couldactbothas thyroid hormone receptors ( transcriptionfactor(Pit1)withERand pituitary-specific This was drivenby changes in the interaction dynamics of to acoactivatorwasrevealedontheratprolactinpromoter. duality in RIP140 function in switching from a corepressor ( Dasgupta &O’Malley2014 metabolism andcancer RIP140 inreproduction, i. 1 Fig. Nautiyal Ikonen Published byBioscientifica Ltd. Initial studiesindicatedacoactivatorroleforRIP140 . Thissignaturesequence(alsocalledNRbox),first Heery ). Coregulatorinteractionswithnuclearreceptors t al et et al et al . 1997 . 2013 Leo &Chen2000 . 1997 (repression) boxes,respectively. are highlightedingreen(activation) andred (OFF switch).Keyprocessesregulated byRIP140 coactivator (ONswitch)aswella corepressor protein (CBP).RIP140canfunctionboth asa histone deacetylase(HDAC)andCREB-binding factors andenzymes,whichmodifyhistones,ie, LXXML) ( (RD1–4) andinteractionmotifs(LXXLL protein showingdifferent knowndomains RIP140 aswitchcoregulator. CartoonofRIP140 Figure 1 , a Joyeux ). Thiselaborateinteractomeisdue , Torchia Downloaded fromBioscientifica.com at09/23/202102:05:05PM Christian ). Chuang t al et et al et al Zschiedrich . 1997 , Christian . 1997 Christian . 2006 et al 58 ). Howeversoon, : . 1997 3 ) withtranscription ). LXXLLmotifs t al et t al et t al et ) as a result . 2006 . 2008 . 2006 LXXLL R148 via freeaccess ) , ,

Review j nautiyal RIP140 in reproduction, 58:3 R149 metabolism and cancer

Rosell et al. 2011, Nautiyal et al. 2013a,b) in some acetylation through histone acetyl transferases (HATs) situations and as a corepressor in others (Christian et al. and E1A-binding protein p300 (p300)/cAMP response 2005, Powelka et al. 2006, Debevec et al. 2007, Seth et al. element-binding protein (CBP) of a N terminal lysine 2007). Although mechanisms describing this dual role are residue on RIP140 led to the disruption of the RIP140– not well understood, the best hypothesis so far is that, this CtBP complex and thus a loss of repressive potential of switch is determined by the cellular environment and is RIP140 (Vo et al. 2001). promoter sequence specific. Gupta and coworkers identified 11 phosphorylation Wei and coworkers presented the first biochemical sites on RIP140 using mass spectrophotometry. evidence that RIP140 possesses a Trichostatin A-sensitive By studying constitutively phosphorylated and transrepressive activity and could directly recruit dephosphorylated mutants of RIP140 at different sites, histone deacetylases (HDAC) 1 and 3 both in vivo and this study reported that the strength of the repressive in vitro. The HDAC-interacting domain on RIP140 was potential of RIP140 through HDACs is determined by mapped to its N terminus between amino acids 78 and its phosphorylation status. For example, a constitutive 303 (Wei et al. 2000). HDACs are enzymes responsible dephosphorylation at Thr202 and Thr207 on RIP140, for the removal of the acetyl group on the lysines and significantly impaired its repressive activity and HDAC restoration of the DNA–histone attractive forces, leading recruitment, whereas the opposite effects were seen to a closed chromatin confirmation. 4 classes of HDACs, with a constitutive phosphorylation of these residues representing about 18 enzymes are known. Of these, (Gupta et al. 2005). Further threonine phosphorylation HDACs belonging to classes I, II and IV share a related of RIP140 by Erk2, which promoted p300 recruitment catalytic mechanism involving a zinc metal ion and do for lysine acetylation on RIP140, enhanced its repressive not require any cofactor. Members of class III HDACs, activity. This was shown to influence fat accumulation which include sirtuins 1–7, employ a NAD+ dependent in differentiated adipocytes (Ho et al. 2008). These mechanism (Dawson & Kouzarides 2012). HDACs are studies indicate how post-translational modifications frequently recruited to nuclear receptors by direct on RIP140 regulate its potential to act as a corepressor. binding or brought to the site of transcription by other Apart from the interactions with HDACs, several studies primary coregulators such as RIP140 (Heinzel et al. 1997, also suggested that the repressive mechanism of action of Nagy et al. 1997, Christian et al. 2006, Kato et al. 2011). RIP140 is through competition with coactivators like SRC1 Using deletion mutants, Christian and coworkers (Treuter et al. 1998) and p300/CBP-associated protein identified 4 distinct autonomous repression domains (RD) (PCAF) (Chen et al. 2004, Gupta et al. 2007). Corepressors

Journal of Molecular Endocrinology RD1–RD4 in RIP140 (Christian et al. 2004). These RDs NCOR1 and SMRT-1 also act by recruiting HDAC proteins provide platforms for different corepressor complexes. and have specialised domains called the SANT domains Both RD1 and RD2 act by recruiting HDACs (Wei et al. through which they modulate the activities of HDACs 2000). Recruitment of HDACs to RD2 is mediated by and help in recognising histones in context with other corepressor, C-terminal-binding protein (CtBP). As proteins. The binding sites of several nuclear receptors repression is only relieved partially by HDAC inhibitor and transcription factors on NCOR1 and SMRT have been Trichostatin A, it is believed that CtBP acts by HDAC- mapped extensively (Wong et al. 2014). dependent as well as -independent mechanisms. Four With the background knowledge of corepressive CtBP-binding motifs have been identified in RIP140 functions of RIP140, the first mechanistic explanation protein. Castet and coworkers identified the PIDLS and to its coactivating function came from Stefan Herzig’s PINLS motifs, which are CtBP-binding motifs on RIP140 laboratory. Although an intrinsic activation function and demonstrated that RIP140 also interacts with HDAC within RIP140 has not been found so far, this study 5. This interaction was mapped to the N terminus between reported that RIP140 activates the expression of several residues 27 and 199 on RIP140 (Castet et al. 2004). As inflammatory cytokines in macrophages by coactivating CtBP is a functional dehydrogenase that is sensitive to the NFκB subunit RelA. This is achieved as a result of NADH:NAD redox ratio, an increase in this ratio may interaction of RIP140 with the C-terminus, of CBP promote repression mediated by RIP140 (Christian et al. through its RD1 domain (Zschiedrich et al. 2008). 2006). Thus, repression brought about by RIP140 is RIP140 was further shown to coactivate CREB-mediated likely to be influenced by the redox status of the cells. transcription on the amphiregulin (Areg) promoter in Interactions between RIP140 and CtBP are regulated by the ovarian granulosa cells, and recent mapping of the post-translational modifications on RIP140. For example, RIP140-binding sites in breast cancer cells have shown

http://jme.endocrinology-journals.org © 2017 Society for Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/JME-16-0156 Printed in Great Britain Downloaded from Bioscientifica.com at 09/23/2021 02:05:05PM via free access Journal of Molecular Endocrinology 2013 gonadal axis( to theexaminationof hypothalamic–pituitary– ( oestrus cycle( ( levels ofcirculating insulin-likegrowthfactor-1(IGF1) maturation, whichislinkedwithageingandtoreduced RIPKO femalemiceshowadelayedonsetofsexual Female fertilityandmammaryglanddevelopment adipose tissue. of itsroleincarcinogenesis andmetabolicfunctionsin responsive femalereproductivetissuesandrecentfindings following sectionsdescribeRIP140biologyinhormone- Rosell cancer ( the pathophysiologyofageing( 2012 2013 Ho 2012 Berriel Diaz ( 2008 ( 2010 ( its genetargetsinovary roleofRIP140and helped inunravellingtheregulatory counterparts ( and femalemiceweresignificantlyleanerthantheirWT to ovulate( Female RIPKOmicewereinfertilebecauseofaninability significant phenotypescametolightinRIPKOmice:(i) transgenic (RIPTg)mice( 2000 RIP140, i.e.theRIP140knockout(RIPKO)( from studies on genetically modified mouse modelsof Knowledge ofthebiologicalfunctionsRIP140came Biological functionsofRIP140 (PRMT1) ( (CARM1) and protein arginine N methyl transferase and pCAFAD2recruitsargininemethyltransferase coactivators oftheSRCfamily. AD1recruitsCBP/p300 C-terminal activationdomains(AD1/2)arepresentin sites ( that CBPandp300co-occupyseveralRIP140-binding Seth Christian White Yuan DOI: 10.1530/JME-16-0156 http://jme.endocrinology-journals.org Review t al et , b cells( ), inflammatory , ), uterus( ) and constitutively overexpressing RIP140 b et al Nautiyal ), neuralfunctions( ) andstudieswerecarried outtoexamine et al et al Feng Park Docquier t al et . 2007 Rollins . 2012 . 2014 et al . 2012 et al White t al et t al et . 2000 Leonardsson et al . 2005 Nautiyal Leonardsson , Leonardsson . 2008 Fritah , ), mammary gland( ), mammary et al . 2009 ). Althoughthesemicehaveanormal Aziz . 2014 et al . 2010 et al , ). The infertility phenotype led ), heart( . 2015 . 2013 et al et al Powelka . 2000 , et al , , Tullet Rosell . 2012 . 2015 Persaud 2015 Tsai ). t al et , Fritah t al et t al et . 2013 ) and(ii)bothRIPKOmale Fritah Lapierre Zschiedrich et al et al ) andmorerecentlyin t al et ), liver( , et al . 2004 j

Gibson . 2002 . 2002 nautiyal Yuan © 2017SocietyforEndocrinology t al et . 2006 . 2005 b et al . 2009 . 2014 t al et ), theyareinfertile et al ). Further studies Herzog . 2011 t al et ), adiposetissue , . 2011 Nautiyal et al Printed inGreatBritain , , Nautiyal . 2010 , . 2014 ). Two distinct Hallberg Nautiyal t al et Duclot . 2012 White . 2016 , Chen et al ), muscle , . 2008 ). Two 2015 . 2007 t al et ). The ) and t al et t al et t al et et al et al et al a . . . , . , . , . .

epiregulin (EREG)andbetacellulin(BTC)( factor family, whichincludesamphiregulin(AREG), and expressioninRIPKOmiceoftheEGF-likegrowth demonstrated defectsinthetranscriptionalregulation phenotype ( retained oocytesthusexplainingtheanovulatory However, itwasremarkablethatthecorporalutea these micepointingtowardsnormalluteinisation. inDifferentiated corporaluteawerealsoobserved stage,indicatingnormalfolliculogenesis.ovulatory developmental stagesfromprimordialtothepre- ovaries ofmatureRIPKOmicerevealedfolliclesatall gland ( uterus ( the ovaries( of theEGF-likegrowthfactor family( that RIP140isessentialfor the expressionofthesegenes one oftheearliesteventsafterluteinisinghormone follicleisof thesegrowthfactorsinthepre-ovulatory 2005 2002 2010 rescue several enzymesinvolved in theprocessbutdidnot in vitro that exposureofRIPKOCOCstorecombinantAREG Richards &Pangas2010 cumulus expansion( expression ofseveraldownstreamenzymesthatpromote manner andregulatetheirownexpressionaswell as family membersareknowntoactinautocrine–paracrine matrix. AftertheLHsurge,EGF-likegrowthfactor of genesinvolvedinthesynthesiscumulus rescued cumulusexpansionanddownstreamexpression (COCs) torecombinantAREGboth Exposure oftheRIPKOcumulus-oocytecomplexes thus adefectivecumulusexpansion( failed toshowexpressionofEGFfamilymembersand process ( showdefectsinthisare reportedtobeannovulatory is essentialforovulationandseveralmousemodelsthat loosen upandthusexpand( the initiallycompactlypackedcumulusgranulosacells their productsconstituteasecretedmatrixonwhich from thecumulusgranulosacellsgetexpressed,and where aseriesofdownstreamenzymesandfactors follicleprocesses aftertheLHsurge,inpre-ovulatory Cumulus expansionisabiochemicalsequenceof initiates acascadeofeventscalledcumulusexpansion. (LH) surge ( metabolism andcancer RIP140 inreproduction, Published byBioscientifica Ltd. , , ). Analysisof Nautiyal Areg rescuedcumulusexpansionandexpressionof Nautiyal Tullet Leonardsson Richards 2007 expressionorthatof Park White White t al et et al et al t al et Areg . 2010 . 2005 Richards 2007 . 2004 . 2013 t al et t al et promoteringranulosacell lines ). Pre-ovulatory RIPKOfollicles). Pre-ovulatory t al et Downloaded fromBioscientifica.com at09/23/202102:05:05PM ). Itwasnoteworthy, however, ). In WT mice, the expression . 2000 ). Expression of these factors . 2000 , Fig. 2 b . 2002 ). Cross-sectionsthrough Nautiyal Ereg ). Cumulusexpansion , , ). Further studies Shimada Leonardsson ) andmammary in vitro and 58 Tullet : 3 Nautiyal t al et Btc and et al Tullet indicating et al . 2010 . 2005 . 2006 R150 in vivo t al et t al et t al et via freeaccess ), ), ). ). . , . .

Review j nautiyal RIP140 in reproduction, 58:3 R151 metabolism and cancer

Figure 2 Biological processes regulated by RIP140. Ovary: Pre-ovulatory follicles with granulosa cells (pink) lining the follicle. The cumulus oocyte complex, which is the oocyte surrounded by cumulus granulosa cells (darker blue) is shown in an unexpanded state on left. After the LH surge, RIP140 activates amphiregulin (Areg) expression, which further activates downstream enzymes that synthesise the cumulus matrix. This results in cumulus expansion,

Journal of Molecular Endocrinology i.e., cumulus granulosa cells spread on a self-synthesised matrix (lighter blue cells), shown on right (Nautiyal et al. 2010, Ochsner et al. 2003a,b). Mammary gland: Shown on the left is a mammary fat pad with rudimentary epithelium at the base representing a pre-pubertal mouse mammary gland. RIP140 activates mitogens and factors that are essential for mammary gland development, side branching and differentiation (Right). These factors include Areg, PGR, STAT5a and Ccnd1, which are all ER target genes that are coactivated by RIP140 in the mammary gland (Nautiyal et al. 2013a,b). Adipose tissue: (Extreme left) Fat storing WAT that is composed of adipocytes and M2 macrophages. WAT adipocytes expand in size on exposure to high-fat diet to meet the increasing demands of fat storage and also have an increased infiltration of macrophages, which are of the M1 (i.e., inflammatory type). Loss of RIP140 promotes the formation of BAT. RIP140 KO animals are lean and show a BAT adipose phenotype. BAT (extreme right) has smaller fat droplets and is abundant in mitochondria and generates heat. Loss of RIP140 from macrophages promotes the formation of Beige fat depots, which are adipocytes within the WAT that are intermediary between WAT and BAT. This is called ‘browning of fat,’ which is promoted by loss of RIP140 (Liu et al. 2015b).

demonstrated that RIP140 regulates gene expression restored by ovarian correction, the uterus and mammary of this growth factor by coactivating CREB and cJun gland in these mice required closer examination. transcription factors (Nautiyal et al. 2010). Ovarian and RIPKO mice show clear defects in the mammary embryo transplant experiments in RIPKO mice resulted ductal elongation at puberty with adult mice developing in only partial restoration of fertility (Leonardsson et al. a scanty epithelial network. Conversely, RIPTg mice 2002). About 50% of the embryos that were transplanted show precocious growth with extensive cell division and were resorbed at post coitum day 13.5, indicating an side branching and develop ductal hyperplasia in the inadequate uterine environment to support developing mammary gland (Nautiyal et al. 2013b). RIPTg mice have embryos, and most of the pups were still born or died been reported to develop rapid, progressive postnatal soon thereafter (Leonardsson et al. 2002), suggesting an cardiomyopathy. Examination of the heart tissue in these inability to survive in the absence of maternal feeding. mice demonstrated mitochondrial degeneration and This indicated that although fertility could be partially reduced expression of genes involved in mitochondrial

http://jme.endocrinology-journals.org © 2017 Society for Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/JME-16-0156 Printed in Great Britain Downloaded from Bioscientifica.com at 09/23/2021 02:05:05PM via free access Journal of Molecular Endocrinology by ER and its interaction partners FOXA1, GATA3 line. 82%oftheRIP140-binding siteswereco-occupied map RIP140bindingwithER inMCF7breastcancercell Docquier ( implicated theinvolvementofRIP140inbreastcancer in ER-mediatedgenetranscription.Initialreportshad further mechanisticunderstandingofitsinvolvement gland developmentasacoactivatorforERwarranted Insights obtainedabouttheroleofRIP140inmammary Carcinogenesis glandremainstobeexplored. in themammary potentialwithothertranscription factors its coregulatory genes coregulated by RIP140, it is worth mentioning that Although workherewasmainlydonetolookatERtarget gland. RIP140 levelsdeterminecellfateinthemammary or blocksdifferentiation( ones indicatingthatRIP140promotesproliferationand/ an increaseintheprogenitorcellsoverdifferentiated stem cells.Within theluminalcellpopulation, therewas glandisconsideredhomeformulti-potent mammary This isinterestingasthebasalcellcompartmentof cellpopulation. to anincreaseinthebasalmammary mice demonstratedthatRIP140overexpressionleads 2013 and ActivatorofTranscription ( ( RIP140. Thesegenesincluded that wereERtargetsandtranscriptionallycoactivatedby glanddevelopment important regulatorsofmammary tissuehelpedinfindingseveral in themousemammary development. GlobalChIP-seqanalysisofERbindingsites gland in stromal–epithelialcrosstalkmammary is warrantedtoobtainfurthermechanisticinsights RIP140 inisolatedstromalandepithelialcellpopulations ( glanddevelopment as wellstromaformammary epithelium RIP140 expressionisessentialinmammary and RIPTgmousemodelshelpedinhighlightingthat recombinant studies at pre-pubertal stages in the RIPKO gland( of themammary and stromalcellsisessentialforthenormaldevelopment Paracrine signalling and crosstalk between epithelium tumourigenesis. could notbeusedtostudymammary a resultofcardiacdefects,RIPTgmicedieearlyandthus related receptorsERR signalling ofnuclearreceptors,PPAR activity, fattyacidmetabolismandtransportimpaired Pgr Nautiyal Oh DOI: 10.1530/JME-16-0156 http://jme.endocrinology-journals.org Review ), cyclinD1( b t al et ). Analysis of mammary cellpopulationsfromRIPTg ). Analysisofmammary . 2006 et al t al et . 2012 . 2013 , ccnd1 Lee ). ChIP-seqanalysiswasperformed to α ), t al et b andERR c-Myc ). Determining gene targets of . 2007 Nautiyal ( Areg Myc Sternlicht 2005 γ j , (

Stat5a nautiyal ) andSignalTransducer , progesteronereceptor Hannafon Fritah © 2017SocietyforEndocrinology t al et α , PPAR ) ( . 2013 Printed inGreatBritain t al et Nautiyal δ , oestrogen- t al et . 2010 ). Tissue b ). Thus, . 2011 t al et ). As , .

responsive genesignature( good outcomerepresentedcaseswithless-activeRIP140- expression signature,whereastheclusterrepresenting poor outcomecorrelatedwithactiveRIP140gene tamoxifen treatment.Patientsintheclusterrepresenting stratify patientswithbreastcancer, whoreceivedadjuvant gene expression classifier that could be successfully used to knockdown intheMCF7cellswereusedtogeneratea proliferation. GenesthatchangedasaresultofRIP140 gene regulation, which stimulated breast cancer cell for ER-mediatedtranscriptionalcomplexformationand knockdown experimentsrevealedthatRIP140isrequired regions ( the restwasenrichedinintronsanddistal intergenic RIP140 binding was seen at the promoters, whereas ( being anenhancer-specificepigeneticmarkofERbinding H3K4me1-demarcated regionsinthegenome,H3K4me1 and othercoactivatorsp300,CBPp160familyat in theintestine,whereas overexpressingRIPTgmice RIPKO micedemonstratedimproved regenerativecapacity When miceweresubjected towholebodyirradiation, apoptosis andthusinfluencing intestinalhomeostasis. intestinal epitheliumbyregulating cellproliferationand mice demonstratedthatRIP140inhibitstherenewal of in coloncancer. Examination of RIPKO and RIPTg a tumoursuppressorroleforRIP140hasbeensuggested chemotherapeutic agents( that RIP140 is involved in sensitisation of these cells to been demonstrated in a study using ovarian cancer cells activation oftheERE( effect exertedbyER siRNA knockdownofRIP140abolishedtherepressive was increasedrecruitmentofRIP140ontheERE,and (ERE) luciferasereporter. With ER stably integratedwithanoestrogenresponseelement cellular proliferationinER-positiveovariancancercells, as acorepressorofER appreciated, Docquierandcoworkershighlighteditsrole cell growth( that RIP140 knockdown induced apoptosis and inhibited Analysis ofseveralbreastcancercellularmodelsshowed any tumours,withtheexceptionofsmallerskintumours. DMBA exposurefor6 weeks, RIPKOmicedidnotdevelop gland, liver andintestinal tract after in skin,mammary counterparts. AlthoughWTmicedevelopedtumours (DMBA)-induced carcinogenesis comparedtotheirWT were lesssusceptibleto7,12-dimethylbenz[a]anthracene coworkers demonstratedthatRIP140-deficientmice metabolism andcancer RIP140 inreproduction, Joseph Published byBioscientifica Ltd. Although theroleofRIP140asacoactivatorforERis t al et Fullwood Aziz . 2010 et al ). Very similartoER,only5%ofthe t al et β . 2015 β intheregulationofE2-mediated andinantagonisingE2-mediated . 2009 Docquier Downloaded fromBioscientifica.com at09/23/202102:05:05PM Lapierre ). Rosell , Rosell t al et β overexpression,there t al et et al . 2013 58 t al et . 2015 . 2014 : 3 . 2014 ). Ithasalso b ). Azizand ). Recently, ). siRNA R152 via freeaccess Review j nautiyal RIP140 in reproduction, 58:3 R153 metabolism and cancer

had reduced renewal of the intestinal villi compared to use as a biomarker for patient stratification and help in WT counterparts (Lapierre et al. 2014). This was further determining individualised approaches for treatment. confirmed in cellular models in mouse xenografts in which enhanced RIP140 expression reduced colon cancer Metabolic functions in adipose tissue cell proliferation. Clinically, RIP140 mRNA and protein levels were lower in human colon cancer compared to Adipose tissue is an endocrine organ that produces normal tissue, and low RIP140 expression correlated hormones such as E2, leptin, resistin, adiponectin and with poor prognosis. Mechanistically, RIP140 stimulates inflammatory cytokines and is a regulator of energy the transcription of multiprotein β catenin degradation homeostasis (Stern et al. 2016). By regulating adipose complex subunit, adenomatous polyposis coli (APC), composition in the body, RIP140 maintains the balance which inhibits β-Catenin activation in the intestinal between energy storage and expenditure by mechanisms epithelium (Lapierre et al. 2014). Recently, RIP140 that are coming to light now (Kiskinis et al. 2014, Hu et al. has emerged as a prognostic marker in haematologic 2015, Liu et al. 2015b). There are mainly two types of malignancies such as chronic lymphocytic leukaemia adipose tissues. (1) The fat-storing white adipose tissue (CLL) (van’t Veer et al. 2006, Herold et al. 2011). High (WAT), which expands under obese conditions and expression of RIP140 is a favourable prognostic marker in becomes inflammatory, leading to insulin resistance and CLL. The exact mechanisms and pathways regulated by (2) the fat-burning brown adipose tissue (BAT), which is RIP140 in CLL are not known so far. It is speculated that it rich in mitochondria and thus expends energy (Fig. 2). may well be through regulation of nuclear receptors, Wnt Originally, BAT was thought to exist only in neonates, and NFκB signalling pathways (Lapierre et al. 2015a). but it has recently been shown to exist in adult humans Two studies to identify mutations and drivers of (Cypess et al. 2009). endometrial cancer (EC) progression have recently RIPKO mice are lean, with a 70% reduction in body identified several mutations in RIP140, suggesting fat and show resistance to high-fat diet-induced obesity. its role in impaired ER signalling (Ferreira et al. 2014, Although BAT tissue in these mice is histologically Gibson et al. 2016). Microsatellite instability (MSI), normal, the WAT tissue in RIPKO mice shows a significant which is a phenotype caused by mutations in the DNA reduction in the size of the adipocytes (Leonardsson et al. mismatch repair (MMR) genes, is a common feature of 2004). The WAT in RIPKO mice expresses genes that are EC (Cancer Genome Atlas Research Network et al. 2013). more characteristic of brown fat, i.e., involved in increa In a genome-wide search to identify genes effected by sing energy expenditure. These genes include uncoupling

Journal of Molecular Endocrinology MSI, RIP140 was the highest mutated gene (34% of EC) protein 1 (UCP1), cell death-inducing DNA fragmentation (Ferreira et al. 2014). Exome sequencing of EC tumours factor (CIDEA), a lipid droplet protein and carnitine in another study identified RIP140 mutation in a palmitoyl transferase (CPT1), a mitochondrial fatty acid significant number of tumours (12% of EC). Although transporter (Leonardsson et al. 2004, Christian et al. several missense mutations were identified, indel 2005). Studies in genetically modified adipose cellular (single base pair insertion and deletion) mutations models demonstrated that RIP140 acts as a repressor were highly recurrent on Asn516 and Lys728 on RIP140 of catabolic processes such as fatty acid oxidation, (Gibson et al. 2016). Future studies should focus on the oxidative phosphorylation, glycolysis and tricarboxylic functional effects of RIP140 alterations in driving the acid cycle (Powelka et al. 2006) and thus ablation of development of EC. RIP140 leads to the upregulation of gene networks in Based on the examination of patient cohorts and work these pathways and thus expenditure of energy. PGC1α in mouse and cancer cellular models in the previously a transcriptional coactivator first identified and cloned mentioned studies, it is clear that RIP140 plays a role in in BAT by the Speigelman group (Puigserver et al. 1998), tumourigenesis. Just like in physiological conditions, the modulates a number of genes involved in these metabolic ability of RIP140 to act both as a coactivator and corepressor pathways and shares several gene targets with RIP140, based on the cellular milieu and in a transcription factor- the two coregulators antagonising each other’s actions specific context is reflected in cancer as well. For example, (Hallberg et al. 2008, Fernandez-Marcos & Auwerx 2011). RIP140 promotes cancer cell proliferation in breast cancer The existence of a third type of fat namely ‘the beige (Rosell et al. 2014), whereas it inhibits proliferation in fat’ or BRITE has been recently appreciated in WAT. This colon cancer (Lapierre et al. 2014). Further functional and fat has the potential to thrive within the WAT depots on molecular studies in individual cancers will determine its exposure to cold and β2 adrenergic agonist treatment.

http://jme.endocrinology-journals.org © 2017 Society for Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/JME-16-0156 Printed in Great Britain Downloaded from Bioscientifica.com at 09/23/2021 02:05:05PM via free access Journal of Molecular Endocrinology as white adipose tissue underwent browningandas whiteadiposetissue underwent macrophages inmiceledto adiposetissueremodelling in macrophages.RIP140 knockdown specificallyin 2015 M2 polarisationofthemacrophagepopulation( ( the stateofinflammationleadingontoinsulinresistance and alsosecretesfurtherharmfulsubstancesthataggravate enlarges tomeettheincreaseddemandsofenergystorage 2013 and recruitmentoftheM1type( in theM2stateto45–60%dueincreasedinflammation increases from10to15%ofthetotalstromalcells,mostly diet-induced obesitymodel,thenumberofmacrophages represents astateofchronicinflammation.Inhigh-fat homeostasis andinsulinsensitivity, whereastheM1 tissue ( state canvary, basedonthemetabolicsignalsinWAT ( different geneexpressionandtranscriptionalprofiles states, namelyM1andM2.These two statesrepresent different states.Broadly, macrophagescanexistintwo cues, theyarecapableofmakingphenotypicswitchesto remarkable plasticity, and depending on the metabolic ( potentially harmfulapoptoticproductswithprecision cellular debrisgeneratedduringtissueremodellingand as immunecells.Forexample,thesephagocyticcellsclear homeostatic roles,whichareseparatefromtheirfunction of theinnateimmuneresponses,macrophagesplayvital is appreciatedinthis.Apartfrombeingcrucialeffectors conditions, andthe roleof macrophages are inflammatory of PGC1 common genesorbydirectlyregulatingtheexpression by antagonisingthecoactivatorpotentialofPGC1 BRITE depotswithinthewhitefat.Thiscouldeitherbe RIP140 actsisthroughpreventingthedevelopmentof in the regulation of brown fat gene expression. The way in adiposecelllinesindicatedthatRIP140haslittlerole adipocytes. FurtherinvestigationoftheroleRIP140 expression ofbrownadipocytegeneswithinwhite PR domain-containing16(PRDM16)influencethe ( adipocytes showdistinctgeneexpressionsignatures it isworthmentioningthatthebrownandbeige fat, likebrownisinvolvedinthermogenesisalthough This ‘browningoffat’isconsideredbeneficialasbeige Mosser &Edwards2008 Chawla Gautier Walden DOI: 10.1530/JME-16-0156 http://jme.endocrinology-journals.org Review RIP140 hasbeenreportedtotipthebalanceofM1vs Obesity, insulin resistance and metabolic dysregulation ). ThisleadstoremodellingoftheWAT tissue,which b ). High-fatdietincreases RIP140expression Lumeng α et al t al et t al et ( Kiskinis . 2011 . 2012 . 2012 et al , et al Wynn ), and their number and activation . 2007 ) ( i. 2 Fig. . 2014 ). Macrophages are knowntohave ). Forexample,M2maintains et al ). CoregulatorsPGC1 ). . 2013 j

nautiyal © 2017SocietyforEndocrinology Odegaard &Chawla , Liu Printed inGreatBritain et al . 2014 Liu α and ). α et al on on . and high-fatdiet-inducedinsulinresistance( disordersa newtherapeuticstrategyininflammatory RIP140 expressioninmacrophagescouldbeusedas insulin resistance.Thisstudydemonstratedthataltering M2 state and a decrease in M1 state, which improved fat diet conditions with increase inmacrophages macrophage profile in thesemicealtered under high- fat diet-fedconditions.IntheabsenceofRIP140, in high- improved insulin sensitivity was observed Aziz MH,ChenX,ZhangQ,DeFrain C,OslandJ,LuoY, ShiX& References Christian forcriticalreadingofthismanuscript. The author is gratefulto Prof. Malcolm Parker, Prof.Simak Ali andDrMark Acknowledgement the public,commercialornot-for-profit sector. This articledidnotreceiveanyspecificgrantfromfundingagency in Funding perceived asprejudicingtheimpartialityofthisreview. The authorsdeclarethatthereisnoconflictofinterestcouldbe Declaration ofinterest of RIP140willbeexploredinfuturestudies. role of RIP140. The biomarker and therapeutic potential more mechanisticinsightsareneededtoclarifythisdual physiological orpathologicalsettingsaretantalising,and its coactivating and corepressing potential in different potentially even fertility-related pathologies. Reports of progression of cancer, metabolic abnormalities and processes and plays a role in the development and RIP140 isacoregulatorthatdrivescrucialphysiological Concluding remarks macrophages forRIP140expressionandcorrecting the therapeuticpotentialininjectingengineered tissue depotsprovidingaproofofconceptregarding insulin resistanceandbrowningofthewhiteadipose expression in macrophages, led to improvement of from WAT ofmice,whichweredeficientforRIP140 injecting obesemicewithM2macrophagesobtained RIP140 ledtodifferentiationintobeigecells.Likewise from culturesofmacrophages,whicharedeficientin 2014 metabolic dysregulation( metabolism andcancer RIP140 inreproduction, Published byBioscientifica Ltd. Yuan R2015SuppressingNRIP1inhibitsgrowth ofbreastcancer ). Exposureofpreadipocytestomediaobtained Downloaded fromBioscientifica.com at09/23/202102:05:05PM Liu et al . 2015 58 : 3 a ). Liu R154

et al via freeaccess . Review j nautiyal RIP140 in reproduction, 58:3 R155 metabolism and cancer

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Zschiedrich I,HardelandU,Krones-HerzigA,BerrielDiazM, Yuan R,MengQ,NautiyalJ,FlurkeyK,Tsaih SW, KrierR,ParkerMG, York B&O’MalleyBW2010Steroidreceptorcoactivator(SRC)family: Wynn TA, ChawlaA&PollardJW2013Macrophagebiologyin Accepted Preprint published online 10 January 2017 Accepted Preprintpublishedonline10January 2017 Accepted 10January Received infinalform26December2016 metabolism andcancer RIP140 inreproduction, Published byBioscientifica Ltd. 264–276. NFkappaB/RelA-dependent cytokinegeneexpression. Zawatzky R,Yu X, Vegiopoulos A,MuggenburgJ,SombroekD,HofmannTG, pnas.1121113109) among inbredmousestrains. female sexualmaturationandlifespanthroughcirculating IGF1 Harrison DE&PaigenB2012Geneticcoregulationofage 38743–38750. masters ofsystemsbiology. (doi:10.1038/nature12034) development, homeostasisanddisease. Urology and regulation.

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