The AF-1 and AF-2 Domains of RARγ2 and RXRα Cooperate for Triggering the Transactivation and the Degradation of RARγ2/RXRα Heterodimers

In eukaryotic cells, liganded RARγ2/RXRα heterodimers activate the transcription of retinoic acid (RA) target genes and then are degraded through the ubiquitin-proteasome pathway. In this study, we dissected the role of the RARγ2 and RXRα partners as well as of their respective AF-1 and AF-2 domains in the processes of transactivation and degradation. RARγ2 is the “engine” initiating transcription and its own degradation subsequent to ligand binding. Integrity of its AF-2 domain and phosphorylation of its AF-1 domain are required for both the degradation and the transactivation of the receptor. Deletion of the whole AF-1 domain does not impair these processes but shifts the receptor toward other proteolytic pathways through RXRα. In contrast, RXRα plays only a modulatory role, cooperating with RARγ2 through its AF-2 domain and its phosphorylated AF-1 domain in both the transcription activity and the degradation of the RARγ2/RXRα heterodimers. Our results underline that the AF-1 and AF-2 domains of each heterodimer partner cooperate with one other and that this cooperation is relevant for both the transcription and degradation processes. In eukaryotic cells, liganded RARγ2/RXRα heterodimers activate the transcription of retinoic acid (RA) target genes and then are degraded through the ubiquitin-proteasome pathway. In this study, we dissected the role of the RARγ2 and RXRα partners as well as of their respective AF-1 and AF-2 domains in the processes of transactivation and degradation. RARγ2 is the “engine” initiating transcription and its own degradation subsequent to ligand binding. Integrity of its AF-2 domain and phosphorylation of its AF-1 domain are required for both the degradation and the transactivation of the receptor. Deletion of the whole AF-1 domain does not impair these processes but shifts the receptor toward other proteolytic pathways through RXRα. In contrast, RXRα plays only a modulatory role, cooperating with RARγ2 through its AF-2 domain and its phosphorylated AF-1 domain in both the transcription activity and the degradation of the RARγ2/RXRα heterodimers. Our results underline that the AF-1 and AF-2 domains of each heterodimer partner cooperate with one other and that this cooperation is relevant for both the transcription and degradation processes. In response to retinoic acid (RA), 1The abbreviations used are: RA, retinoic acid; RAR, retinoic acid receptor; RXR, retinoic X receptor; AF, activation function domain; CAT, chloramphenicol acetyltransferase; MAPK, mitogen-activated protein kinase; WCE, whole cell extract; WT, wild type; Z, benzyloxycarbonyl; fmk, fluoromethyl ketone; m, mouse.1The abbreviations used are: RA, retinoic acid; RAR, retinoic acid receptor; RXR, retinoic X receptor; AF, activation function domain; CAT, chloramphenicol acetyltransferase; MAPK, mitogen-activated protein kinase; WCE, whole cell extract; WT, wild type; Z, benzyloxycarbonyl; fmk, fluoromethyl ketone; m, mouse. target genes are regulated by two families of nuclear receptors, the RARs (α, β, and γ) and the RXRs (α, β, and γ) that bind as RAR/RXR heterodimers to response elements located in their promoters (1Laudet V. Gronemeyer H. Nuclear Receptor FactsBook. Academic Press, London2001Google Scholar, 2Giguere V. Endocr. Rev. 1999; 20: 689-725Crossref PubMed Scopus (711) Google Scholar, 3Renaud J.P. Moras D. Cell Mol. Life Sci. 2000; 57: 1748-1769Crossref PubMed Scopus (210) Google Scholar). RARs and RXRs are modular proteins (Fig. 1) with a highly conserved central DNA-binding domain and a less conserved ligand-binding domain that is composed of 11 α-helices (H1 and H3-H12), loops, and two short β-strands (Ref. 4Chambon P. FASEB J. 1996; 10: 940-954Crossref PubMed Scopus (2601) Google Scholar and references therein) with a dimerization interface formed mainly by helices H9 and H10 (5Bourguet W. Vivat V. Wurtz J.M. Chambon P. Gronemeyer H. Moras D. Mol. Cell. 2000; 5: 289-298Abstract Full Text Full Text PDF PubMed Scopus (352) Google Scholar). The recent comparison of the crystal structures of the ligand-binding domain of unliganded and liganded RARs and RXRs (1Laudet V. Gronemeyer H. Nuclear Receptor FactsBook. Academic Press, London2001Google Scholar, 6Moras D. Gronemeyer H. Curr. Opin. Cell Biol. 1998; 10: 384-391Crossref PubMed Scopus (704) Google Scholar, 7Egea P.F. Rochel N. Birck C. Vachette P. Timmins P.A. Moras D. J. Mol. Biol. 2001; 307: 557-576Crossref PubMed Scopus (83) Google Scholar) shed light on the molecular mechanism underlying the structural reorganization that accompanies ligand binding. The ligand-induced conformational changes in the ligand-binding domain result in the release of corepressors and in conformational rearrangements that affect mostly the N-terminal part of H3, H11, and the highly conserved amphipathic helix 12, which carries the autonomous activation function AF-2 (8Bourguet W. Germain P. Gronemeyer H. Trends Pharmacol. Sci. 2000; 21: 381-388Abstract Full Text Full Text PDF PubMed Scopus (386) Google Scholar). The new conformation generates an interaction surface for coactivators (9Glass C.K. Rosenfeld M.G. Genes Dev. 2000; 14: 121-141Crossref PubMed Google Scholar), which then recruit multiprotein complexes and lead to the activation of responsive genes (10Dilworth F.J. Chambon P. Oncogene. 2001; 20: 3047-3054Crossref PubMed Scopus (216) Google Scholar, 11McKenna N.J. O'Malley B.W. Cell. 2002; 108: 465-474Abstract Full Text Full Text PDF PubMed Scopus (1247) Google Scholar). Through this surface, RARs also interact with SUG-1 (12Gianni M. Bauer A. Garattini E. Chambon P. Rochette-Egly C. EMBO J. 2002; 21: 3760-3769Crossref PubMed Scopus (132) Google Scholar), which belongs to the 19 S regulatory complex of the 26 S proteasome (13Voges D. Zwickl P. Baumeister W. Annu. Rev. Biochem. 1999; 68: 1015-1068Crossref PubMed Scopus (1592) Google Scholar). In RAR/RXR heterodimers, RXR is subordinated to the nonliganded RAR and therefore cannot autonomously induce transcription upon binding of a cognate agonist (14Germain P. Iyer J. Zechel C. Gronemeyer H. Nature. 2002; 415: 187-192Crossref PubMed Scopus (266) Google Scholar). However, in the presence of both RAR and RXR ligands, RXR synergizes with RAR for the recruitment of coactivators and thus for the transcription of RA target genes. The N-terminal region of RARs and RXRs contains another transcription activation domain called AF-1, which acts autonomously and ligand-independently (15Nagpal S. Friant S. Nakshatri H. Chambon P. EMBO J. 1993; 12: 2349-2360Crossref PubMed Scopus (272) Google Scholar). The interesting feature of this AF-1 domain is that it contains consensus phosphorylation sites for proline-dependent kinases (for a review, see Ref. 16Rochette-Egly C. Cell. Signal. 2003; 15: 355-366Crossref PubMed Scopus (237) Google Scholar). The AF-1 domain of unliganded RARγ2 (Fig. 1) is phosphorylated at serine 68 (17Bastien J. Adam-Stitah S. Riedl T. Egly J.M. Chambon P. Rochette-Egly C. J. Biol. Chem. 2000; 275: 21896-21904Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar) by cdk7/cyclin H-associated to transcription factor IIH, a general transcription factor also involved in DNA repair (18Egly J.M. FEBS Lett. 2001; 498: 124-128Crossref PubMed Scopus (107) Google Scholar). Phosphorylation of this serine is required for RA-induced transcription initiation (17Bastien J. Adam-Stitah S. Riedl T. Egly J.M. Chambon P. Rochette-Egly C. J. Biol. Chem. 2000; 275: 21896-21904Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar). In response to RA, however, RARγ2 can also be phosphorylated at the nearby serine 66 by p38MAPK (12Gianni M. Bauer A. Garattini E. Chambon P. Rochette-Egly C. EMBO J. 2002; 21: 3760-3769Crossref PubMed Scopus (132) Google Scholar, 19Gianni M. Kopf E. Bastien J. Oulad-Abdelghani M. Garattini E. Chambon P. Rochette-Egly C. J. Biol. Chem. 2002; 277: 24859-24862Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar). Phosphorylation of RXRα by MAPKs (Fig. 1) at three residues located in the AF-1 domain (Ser-61, Ser-75, and Thr-87) has been also reported (20Adam-Stitah S. Penna L. Chambon P. Rochette-Egly C. J. Biol. Chem. 1999; 274: 18932-18941Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar). We have recently shown that liganded RARγ2 is degraded by the ubiquitin-proteasome pathway when heterodimerized with RXRα and engaged in transcription of RA target genes (12Gianni M. Bauer A. Garattini E. Chambon P. Rochette-Egly C. EMBO J. 2002; 21: 3760-3769Crossref PubMed Scopus (132) Google Scholar) according to the following model. The fraction of RARγ2 that is bound to cognate response elements as heterodimers with RXRα is phosphorylated by the cdk7 subunit of transcription factor IIH and activates transcription, which increases up to 24–48 and then a in transcription is to the RA-induced activity of which to phosphorylation of the AF-1 domain of in phosphorylation acts as a the to RARγ2 degradation through an in its and subsequent by the SUG-1 subunit bound at helix RXRα is also degraded by the proteasome pathway E. Vivat V. The H. Chambon P. Rochette-Egly C. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar, Mol. Cell. Biol. 2001; 21: PubMed Scopus Google Scholar, T. Biochem. Pharmacol. 2001; PubMed Scopus Google Scholar), but this is by its AF-1 domain its phosphorylation both phosphorylation and the also a role in we that phosphorylation of the AF-1 domain a role, on the one the and on the other the receptor to a heterodimer of transcription of the cognate RA target genes and therefore the of In the study, we have RARγ2/RXRα heterodimers, the AF-1 and AF-2 domains of each receptor in to their their own degradation and that of the We that the AF-2 domains of each receptor are for their autonomous degradation. The phosphorylated AF-1 domain of RARγ2 is a of the degradation and the transactivation of both of the whole AF-1 domain does not impair these processes but RARγ2 and its dimerization partner RXRα toward of We also that the AF-1 of RXRα can be phosphorylated in response to phosphorylation has only a modulatory on the degradation of RXRα and its cooperation with RARγ2 for and for and the have been E. Vivat V. The H. Chambon P. Rochette-Egly C. J. 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Penna L. Chambon P. EMBO J. PubMed Scopus Google Scholar). in a as Rochette-Egly C. Penna L. Chambon P. EMBO J. PubMed Scopus Google Scholar). in with in and the according to the in and the the for and of as a and the to for in a with the the and for a in in the presence of RA the agonist the agonist the of both the to and the results as of of and cell as C. S. M. Egly J.M. Chambon P. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). by by and The complexes by according to the and the and to by the and according to which are to The for and and as (12Gianni M. Bauer A. Garattini E. Chambon P. Rochette-Egly C. EMBO J. 2002; 21: 3760-3769Crossref PubMed Scopus (132) Google Scholar, Rochette-Egly C. Penna L. Chambon P. EMBO J. PubMed Scopus Google Scholar). The AF-1 and AF-2 of RARγ2 the of RARγ2/RXRα the activation of RARγ2 the degradation of both partners RARγ2/RXRα heterodimers, with a RARγ2 and a by a in the presence of an RXRα and with RARγ2 and RXRα bound as RARγ2/RXRα heterodimers to the and RA in the degradation of RARγ2 that at (12Gianni M. Bauer A. Garattini E. Chambon P. Rochette-Egly C. EMBO J. 2002; 21: 3760-3769Crossref PubMed Scopus (132) Google Scholar) (Fig. However, in the of degraded less (Fig. that RXRα RARγ2 degradation and that RXRα is in in The degradation of by the proteasome (Fig. but less by the (Fig. with results (12Gianni M. Bauer A. Garattini E. Chambon P. Rochette-Egly C. EMBO J. 2002; 21: 3760-3769Crossref PubMed Scopus (132) Google Scholar, E. Vivat V. The H. Chambon P. Rochette-Egly C. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar), RARγ2 for helix and RARγ2 at the phosphorylation sites located in the AF-1 domain to RA-induced of the presence of RXRα (Fig. we that RARγ2 for its N-terminal AF-1 domain degraded when with RXRα (Fig. However, to RA-induced degradation when in the of RXRα (Fig. when with RXRα at its dimerization surface E. Vivat V. The H. Chambon P. Rochette-Egly C. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar) (Fig. is with the other RAR which does not the phosphorylation sites located in the AF-1 domain for degradation E. Vivat V. The H. Chambon P. Rochette-Egly C. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar). and at the phosphorylation sites degraded as as of RXRα not The degradation of by (Fig. and by (Fig. that of the AF-1 domain RARγ2 toward a proteolytic pathway that is by the proteasome by In cells, RXRα also degraded at of RA its (Fig. (Fig. (Fig. and The only when RXRα heterodimerized with (Fig. The degradation of RXRα by in the of heterodimers with (Fig. and but not with (Fig. and However, in both the of that the of RXRα is to (Fig. and and and results in with the RARγ2 and RXRα in these cells, the degradation of RARγ2 that at of RA (12Gianni M. Bauer A. Garattini E. Chambon P. Rochette-Egly C. EMBO J. 2002; 21: 3760-3769Crossref PubMed Scopus (132) Google Scholar, E. Vivat V. The H. Chambon P. Rochette-Egly C. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar) (Fig. and required the presence of RXRα as not of RARγ2 degradation (Fig. and In with the results with cells, in in the presence of degraded in response to RA (Fig. and degradation by (Fig. and by (Fig. and However, degradation not when in the (Fig. 11 and The of the AF-2 of the through which RXRα in the degradation of of its AF-1 for RXRs The of the AF-1 and AF-2 domains of RXRα the and also with degraded in response to its cognate ligand (Fig. but not in response to the agonist (Fig. The of the two as as the agonist in RARγ2 degradation (Fig. Deletion of the AF-1 AF-2 domains of in and not affect this (Fig. degradation upon binding of its cognate ligand (Fig. but not in response to the agonist (Fig. Deletion of the AF-1 domain of RXRα (Fig. However, the AF-2 domain of RXRα the ligand to degradation (Fig. that the helix of RXRα be of for the of liganded However, the of this domain be upon of the two (Fig. of RA (Fig. one can that the two as well as RA and its cooperate for changes P.F. Rochel N. Birck C. Vachette P. Timmins P.A. Moras D. J. Mol. Biol. 2001; 307: 557-576Crossref PubMed Scopus (83) Google Scholar) that the of the AF-2 domain of RXRα. The of RXRα in to AF-2 the AF-1 of degradation of RXRα heterodimerized with also with also degraded in response to its a agonist (Fig. and not in response to the agonist (Fig. The of the two not the activity of the RXR agonist (Fig. can be autonomously RXRα degradation upon of helix in the RARγ2 partner (Fig. and in the of RARγ2 E. Vivat V. The H. Chambon P. Rochette-Egly C. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar). The degradation of RXRα upon of the AF-2 domain (Fig. that helix is as for the autonomous degradation of RXRα as for that of However, in to the not its degradation be by the liganded partner (Fig. and Deletion of the AF-1 domain also RXRα to its degradation (Fig. of the AF-1 domain of the RARγ2 partner to the (Fig. that the autonomous degradation of RXRα is regulated through the AF-1 domains of both However, in both the upon of the two (Fig. and of RA and Phosphorylation of the AF-1 for the of the AF-1 domain plays a role in the degradation of RXRα and phosphorylation as a for the degradation of proteins A. P.A. Sci. S. A. 1999; PubMed Scopus (83) Google Scholar, C. J.P. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, M. Cell. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, T. Sci. S. A. 2000; PubMed Scopus Google Scholar), RARγ2 (12Gianni M. Bauer A. Garattini E. Chambon P. Rochette-Egly C. 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Chem. 1999; 274: 18932-18941Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar) as it is upon their in the (Fig. RXRα at the phosphorylation sites degraded of RA as as RXRα (Fig. and and and that phosphorylation is not required for the degradation of RXRα RARγ2/RXRα heterodimers. of the RXRα phosphorylation sites not affect the degradation of the RARγ2 (Fig. and However, of the phosphorylation sites RXRα less degraded in response to its agonist (Fig. and as the of the AF-1 be upon of the two (Fig. with RXRα RARγ2 degradation and transactivation are (12Gianni M. Bauer A. Garattini E. Chambon P. Rochette-Egly C. EMBO J. 2002; 21: 3760-3769Crossref PubMed Scopus (132) Google Scholar, 19Gianni M. Kopf E. Bastien J. Oulad-Abdelghani M. Garattini E. Chambon P. Rochette-Egly C. J. Biol. Chem. 2002; 277: 24859-24862Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar), we the activity of and RARγ2/RXRα heterodimers bind to response elements located in the promoters of RA target and upon ligand induce in and a the of a RA a in activity (Fig. less in the of in with the heterodimer for activation of transcription (Fig. In contrast, and of the presence of RXRα (Fig. that the of RARγ2/RXRα heterodimers are on the of the AF-1 and AF-2 domains of with RXRα (Fig. However, to activate transcription when with (Fig. when in the of RXRα (Fig. these results the of the partner not only for the degradation but also for the transactivation of by by the proteasome (Fig. and the that the proteasome can also and transcription M. Rev. Mol. Cell. Biol. 2003; PubMed Scopus Google Scholar). In contrast, transcription by (Fig. and in with the of RXRα (Fig. and The in In these cells, the transactivation of RA target genes as and and a at (Fig. and In with the results with cells, the RA-induced of these genes in (Fig. and and in in a (Fig. and However, it only in in a in the presence of (Fig. and in cells, the RA-induced of these RA target genes in (Fig. and and transcription in both cell (Fig. and and RARγ2 and RXRα for through the Phosphorylation of the AF-1 of through which the activation domains of each partner in the transactivation of RARγ2/RXRα heterodimers by the as that for degradation. heterodimers, liganded RARγ2 is to induce transcription, RXRα is subordinated to (14Germain P. Iyer J. Zechel C. Gronemeyer H. Nature. 2002; 415: 187-192Crossref PubMed Scopus (266) Google Scholar). RXRα cannot autonomously induce transcription in response to its cognate ligand (Fig. 1) but synergizes with liganded (Fig. helix the of RXRα to with RARγ2 (Fig. Deletion of the AF-1 domain of RXRα also the and RXR (Fig. of the three phosphorylation sites located in the AF-1 domain of RXRα the (Fig. In the of heterodimers, transcription by the However, with liganded RXRα that the AF-1 domain of RARγ2 also for this (Fig. is that the autonomous activity of not upon of the AF-1 domain of RXRα (Fig. but to the of the AF-2 domain of RXRα (Fig. that the helix of the partner for the transactivation of liganded However, activity of the heterodimers be in the presence of the two of RA (Fig. RAR/RXR heterodimers (Fig. the AF-2 domain of each partner for the recruitment of multiprotein complexes that in to and and the general transcription to the (10Dilworth F.J. Chambon P. Oncogene. 2001; 20: 3047-3054Crossref PubMed Scopus (216) Google Scholar, 11McKenna N.J. O'Malley B.W. Cell. 2002; 108: 465-474Abstract Full Text Full Text PDF PubMed Scopus (1247) Google Scholar). to recent the AF-1 domains also recruit proteins M. A. Gronemeyer H. Rochette-Egly C. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). we that the AF-1 and AF-2 domains of each partner are elements that cooperate with one other for not only their own activity and degradation but also that of the We also that of one one partner each one on the the complex cooperation the AF-1 and AF-2 domains of each receptor. The AF-2 of RARγ2 but of RXRα for the and of RARγ2/RXRα RARγ2/RXRα heterodimers, both RARγ2 and RXRα are autonomously degraded in response to their cognate through their AF-2 However, the role by the AF-2 domain of each partner is RARγ2 (Fig. the of its AF-2 domain is required for the degradation of the in with that the 26 S proteasome is through this domain (12Gianni M. Bauer A. Garattini E. Chambon P. Rochette-Egly C. EMBO J. 2002; 21: 3760-3769Crossref PubMed Scopus (132) Google Scholar). In RARγ2 degradation is not by the AF-2 domain of a role for the liganded partner in the recruitment of the degradation one can that RXRα RARγ2 degradation through its binding to the cognate response elements C. P. P. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). In contrast, RXRα for this domain not to degradation as it be degraded in response to the ligand of its The of the AF-2 domains of RARγ2 and RXRα in the of the heterodimers is also upon of the AF-2 domain of transcription cannot be by RA in (Fig. In contrast, of the AF-2 domain of the RXRα partner not affect the autonomous activity of RARγ2 but the the two results the according to RAR/RXR heterodimers, liganded RXR is subordinated to the liganded RAR partner for the of and the recruitment of coactivators (14Germain P. Iyer J. Zechel C. Gronemeyer H. Nature. 2002; 415: 187-192Crossref PubMed Scopus (266) Google Scholar). In the AF-2 domain of RARγ2 plays an role as it both transactivation and and its cannot be by the AF-2 of the RXRα In contrast, the AF-2 domain of RXRα to a role as it only with RARγ2 transcription and can be by the AF-2 of RARγ2 in the degradation Phosphorylation of the AF-1 of RARγ2 for the and of RARγ2/RXRα of RXRα a AF-1 domain of RARγ2 is also to the degradation through its phosphorylation and (12Gianni M. Bauer A. Garattini E. Chambon P. Rochette-Egly C. EMBO J. 2002; 21: 3760-3769Crossref PubMed Scopus (132) Google Scholar, E. Vivat V. The H. Chambon P. Rochette-Egly C. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar). is to RA-induced degradation (Fig. when heterodimerized to this RXRα also to that the phosphorylated AF-1 of RARγ2 the degradation of both The phosphorylated AF-1 domain also plays a role in transcription (15Nagpal S. Friant S. Nakshatri H. Chambon P. EMBO J. 1993; 12: 2349-2360Crossref PubMed Scopus (272) Google Scholar, J. Adam-Stitah S. Riedl T. Egly J.M. Chambon P. Rochette-Egly C. J. Biol. Chem. 2000; 275: 21896-21904Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar), through the recruitment of coactivators in cooperation with the AF-2 as for M. A. Gronemeyer H. Rochette-Egly C. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar) and other nuclear A. V. Mol. Cell. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, S. C. Sci. S. A. 1999; PubMed Scopus Google Scholar) with the RXRα partner and Our results also a role for the AF-1 domain of through its in the degradation and transactivation of the heterodimers. We that RXRα to RA through an in the phosphorylation of its AF-1 However, the role of this phosphorylated AF-1 domain (Fig. that of RARγ2 as it is not but its own degradation as well as its cooperation with its partner for of the phosphorylation sites to the of the AF-1 not the degradation of the RARγ2 it not RXRα to degradation. However, RXRα degradation autonomous and required the of its liganded one can that the phosphorylation sites located in the AF-1 domain of RXRα cooperate with for the recruitment the of the degradation and that this can be by liganded of the RXRα phosphorylation sites not affect the of RARγ2/RXRα heterodimers to RA target genes. However, it RXRα to with liganded RARγ2 for transcription, that not only the AF-2 domain but also the phosphorylation sites located in the AF-1 domain of RXRα cooperate with for the recruitment of and Deletion of the AF-1 RARγ2 to RA-induced but on of this is that upon of the whole AF-1 domain of the degradation and the of the heterodimers not but regulated through molecular (Fig. required the AF-2 domain of RXRα to activate transcription and to be degraded in response to its cognate However, in the of this both processes in response to the of both the and RXR to changes P.F. Rochel N. Birck C. Vachette P. Timmins P.A. Moras D. J. Mol. Biol. 2001; 307: 557-576Crossref PubMed Scopus (83) Google Scholar). In that the degradation of RXRα WT, also required by the two liganded of the AF-1 domain RARγ2 on its degradation not the proteasome but involved other that to be in to the of the RARγ2 phosphorylation sites that the heterodimers to of the whole AF-1 domain shifts the toward other proteolytic pathways through RXRα. to with liganded RXRα for transcription, that not only the AF-2 domain but also the AF-1 domain of RARγ2 with RXRα for the recruitment of and In results the role by the phosphorylated AF-1 domain of RARγ2 in the autonomous degradation of each partner and their cooperation for by P. T. Nature. 2001; PubMed Scopus Google Scholar) are to F.J. Oncogene. 2002; 21: PubMed Scopus Google Scholar), it is to that the phosphorylation of RARs RXRs is in these cells, to an degradation of the and a transcription of the RA target genes. in the these we are which proteins are with the AF-1 domains of RARγ2 and RXRα. We J. Bastien and S. for the We are to Bauer for We E. J. H. D. and P. Chambon for cell We also of the cell and for

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