SUG-1 Plays Proteolytic and Non-proteolytic Roles in the Control of Retinoic Acid Target Genes via Its Interaction with SRC-3

Abstract

Nuclear retinoic acid receptor α (RARα) activates gene expression through dynamic interactions with coregulatory protein complexes, the assembly of which is directed by the ligand and the AF-2 domain of RARα. Then RARα and its coactivator SRC-3 are degraded by the proteasome. Recently it has emerged that the proteasome also plays a key role in RARα-mediated transcription. Here we show that SUG-1, one of the six ATPases of the 19 S regulatory complex of the 26 S proteasome, interacts with SRC-3, is recruited at the promoters of retinoic acid (RA) target genes, and thereby participates to their transcription. In addition, SUG-1 also mediates the proteasomal degradation of SRC-3. However, when present in excess amounts, SUG-1 blocks the activation of RARα target genes and the degradation of RARα that occurs in response to RA, via its ability to interfere with the recruitment of SRC-3 and other coregulators at the AF-2 domain of RARα. We propose a model in which the ratio between SUG-1 and SRC-3 is crucial for the control of RARα functioning. This study provides new insights into how SUG-1 has a unique role in linking the transcription and degradation processes via its ability to interact with SRC-3. Nuclear retinoic acid receptor α (RARα) activates gene expression through dynamic interactions with coregulatory protein complexes, the assembly of which is directed by the ligand and the AF-2 domain of RARα. Then RARα and its coactivator SRC-3 are degraded by the proteasome. Recently it has emerged that the proteasome also plays a key role in RARα-mediated transcription. Here we show that SUG-1, one of the six ATPases of the 19 S regulatory complex of the 26 S proteasome, interacts with SRC-3, is recruited at the promoters of retinoic acid (RA) target genes, and thereby participates to their transcription. In addition, SUG-1 also mediates the proteasomal degradation of SRC-3. However, when present in excess amounts, SUG-1 blocks the activation of RARα target genes and the degradation of RARα that occurs in response to RA, via its ability to interfere with the recruitment of SRC-3 and other coregulators at the AF-2 domain of RARα. We propose a model in which the ratio between SUG-1 and SRC-3 is crucial for the control of RARα functioning. This study provides new insights into how SUG-1 has a unique role in linking the transcription and degradation processes via its ability to interact with SRC-3. Retinoic acid (RA) 6The abbreviations used are: RA, retinoic acid; RAR, RA receptor; RXR, retinoid X receptor; SRC, steroid receptor coactivator; GST, glutathione S-transferase; ChIP, chromatin immunoprecipitation; siRNA, small interfering RNA; Re-ChIP, sequential ChIP; RT, reverse transcription; qRT, quantitative RT; RARE, RA response element. influences the proliferation, differentiation, and apoptosis of a variety of cell types through modifications in the expression of subsets of target genes. The RA response is mediated by two classes of nuclear receptors, RARs (α, β, and γ) and RXRs (α, β, and γ), which function as ligand-dependent heterodimeric RAR/RXR transcription activators (1Germain P. Staels B. Dacquet C. Spedding M. Laudet V. Pharmacol. Rev. 2006; 58: 685-704Crossref PubMed Scopus (461) Google Scholar, 2Laudet V. Gronemeyer H. Nuclear Receptor Factsbook. Academic Press, London2001Google Scholar). The basic mechanism of RARs transcriptional activity relies on their ability to bind to cognate DNA response elements located in the promoters of target genes and to undergo major conformational changes subsequently to ligand binding (3Chambon P. FASEB J. 1996; 10: 940-954Crossref PubMed Scopus (2604) Google Scholar). The most striking change observed upon ligand binding is the swing of helix 12 named AF-2 located at the C-terminal end of the ligand binding domain, which generates a new interaction surface for coactivators, which include the steroid receptor coactivator (SRC)/p160 family (SRC-1/NCoA1, SRC-2/TIF2/GRIP-1, and SRC-3/p/CIP/RAC3/ACTR/AIB-1/TRAM-1) and p300/CBP (4Glass C.K. Rosenfeld M.G. Genes Dev. 2000; 14: 121-141Crossref PubMed Google Scholar, 5Lefebvre P. Martin P.J. Flajollet S. Dedieu S. Billaut X. Lefebvre B. Vitam. Horm. 2005; 70: 199-264Crossref PubMed Scopus (111) Google Scholar). These coactivators then recruit a battery of intermediary proteins, including chromatin remodelers and modifiers that act in a coordinated and combinatorial manner to decompact chromatin and direct RNA polymerase II and the general transcription factors to the promoter (6Rochette-Egly C. J. Biol. Chem. 2005; 280: 32565-32568Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar, 7Rosenfeld M.G. Lunyak V.V. Glass C.K. Genes Dev. 2006; 20: 1405-1428Crossref PubMed Scopus (770) Google Scholar, 8Dilworth F.J. Chambon P. Oncogene. 2001; 20: 3047-3054Crossref PubMed Scopus (216) Google Scholar). Emerging evidence indicates that the proteasome system plays an important role in transcription of nuclear receptor target genes (9Lonard D.M. O'Malley B.W. Trends Biochem. Sci. 2005; 30: 126-132Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar, 10Reid G. Hubner M.R. Metivier R. Brand H. Denger S. Manu D. Beaudouin J. Ellenberg J. Gannon F. Mol. Cell. 2003; 11: 695-707Abstract Full Text Full Text PDF PubMed Scopus (621) Google Scholar, 11Bastien J. Rochette-Egly C. Gene (Amst.). 2004; 328: 1-16Crossref PubMed Scopus (606) Google Scholar, 12Kinyamu H.K. Chen J. Archer T.K. J. Mol. Endocrinol. 2005; 34: 281-297Crossref PubMed Scopus (79) Google Scholar). The 26 S proteasome is composed of a 20 S proteolytic core and a 19 S regulatory complex that consists of a lid and a base of six subunits with ATPase activity. These ATPases recognize the ubiquitinated proteins and direct them to the 20 S core for subsequent degradation (reviewed in Ref. 13Pickart C.M. Cohen R.E. Nat. Rev. Mol. Cell. Biol. 2004; 5: 177-187Crossref PubMed Scopus (606) Google Scholar). However, mounting evidence indicates that the proteasome also plays a role in transcription through mechanisms that do not involve proteolysis (14Muratani M. Tansey W.P. Nat. Rev. Mol. Cell. Biol. 2003; 4: 192-201Crossref PubMed Scopus (677) Google Scholar, 15Collins G.A. Tansey W.P. Curr. Opin. Genet. Dev. 2006; 16: 197-202Crossref PubMed Scopus (213) Google Scholar, 16Demartino G.N. Gillette T.G. Cell. 2007; 129: 659-662Abstract Full Text Full Text PDF PubMed Scopus (188) Google Scholar). The 26 S proteasome is involved in the degradation of RARs (17Gianni M. Bauer A. Garattini E. Chambon P. Rochette-Egly C. EMBO J. 2002; 21: 3760-3769Crossref PubMed Scopus (132) Google Scholar, 18Kopf E. Plassat J.L. Vivat V. de The H. Chambon P. Rochette-Egly C. J. Biol. Chem. 2000; 275: 33280-33288Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar), corepressors (19Perissi V. Scafoglio C. Zhang J. Ohgi K.A. Rose D.W. Glass C.K. Rosenfeld M.G. Mol. Cell. 2008; 29: 755-766Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar), and coactivators such as SRC-3 (20Gianni M. Parrella E. Raska I. Gaillard E. Nigro E.A. Gaudon C. Garattini E. Rochette-Egly C. EMBO J. 2006; 25: 739-751Crossref PubMed Scopus (72) Google Scholar) that occurs in response to RA, but its relevance in RAR-mediated transcription is not yet clear (11Bastien J. Rochette-Egly C. Gene (Amst.). 2004; 328: 1-16Crossref PubMed Scopus (606) Google Scholar, 21Bour G. Lalevee S. Rochette-Egly C. Trends Cell Biol. 2007; 17: 302-309Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar). Here we identified a new mechanism underlying the regulation of RARα target genes, in which SUG-1, one of the six AAA ATPases of the 19 S regulatory complex of the 26 S proteasome, links the transcription and degradation processes via its ability to interact with the p160 coactivator SRC-3. Plasmids and Reagents-The pSG5-based expression vectors for mouse (m) RARα1, mRARαΔH12, mSUG-1, and human (h) SRC-1 were previously described (18Kopf E. Plassat J.L. Vivat V. de The H. Chambon P. Rochette-Egly C. J. Biol. Chem. 2000; 275: 33280-33288Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar, 20Gianni M. Parrella E. Raska I. Gaillard E. Nigro E.A. Gaudon C. Garattini E. Rochette-Egly C. EMBO J. 2006; 25: 739-751Crossref PubMed Scopus (72) Google Scholar, 22vom Baur E. Zechel C. Heery D. Heine M.J. Garnier J.M. Vivat V. Le Douarin B. Gronemeyer H. Chambon P. Losson R. EMBO J. 1996; 15: 110-124Crossref PubMed Scopus (350) Google Scholar) as well as the vector encoding B10-HA-FLAG-tagged SRC-3 and the DR5-tk–Luc reporter gene (20Gianni M. Parrella E. Raska I. Gaillard E. Nigro E.A. Gaudon C. Garattini E. Rochette-Egly C. EMBO J. 2006; 25: 739-751Crossref PubMed Scopus (72) Google Scholar). The prokaryotic vector encoding SUG-1 fused to GST in the pGEX-2T plasmid was described before (22vom Baur E. Zechel C. Heery D. Heine M.J. Garnier J.M. Vivat V. Le Douarin B. Gronemeyer H. Chambon P. Losson R. EMBO J. 1996; 15: 110-124Crossref PubMed Scopus (350) Google Scholar). All trans-RA was from Sigma-Aldrich. Antibodies-Monoclonal antibodies against the AB region of RARα (MAb10α (AB)), SUG-1, and polyclonal antibodies against the F region of RARα (RPα (F)) were previously described (18Kopf E. Plassat J.L. Vivat V. de The H. Chambon P. Rochette-Egly C. J. Biol. Chem. 2000; 275: 33280-33288Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar, 20Gianni M. Parrella E. Raska I. Gaillard E. Nigro E.A. Gaudon C. Garattini E. Rochette-Egly C. EMBO J. 2006; 25: 739-751Crossref PubMed Scopus (72) Google Scholar, 22vom Baur E. Zechel C. Heery D. Heine M.J. Garnier J.M. Vivat V. Le Douarin B. Gronemeyer H. Chambon P. Losson R. EMBO J. 1996; 15: 110-124Crossref PubMed Scopus (350) Google Scholar). Mouse monoclonal antibodies against SRC-3 and SRC-2 were from BD Transduction Laboratories. Those against SRC-1 were from Affinity Bioreagents. Anti-FLAG antibodies were from Sigma. Antibodies against β-actin (C-11) were from Santa Cruz Biotechnology (Santa Cruz, CA). The rabbit polyclonal antibodies against RARα (C-20) and SRC-3 used in the ChIP experiments were from Santa Cruz Biotechnology, whereas those against SUG-1 were from Biomol Research Laboratories. Cells, Transfections, Immunoprecipitations, and Immunoblotting-MCF7, HeLa, and COS-1 cells were cultured under standard conditions and transiently transfected using the DMRIE-C reagent, according to the manufacturer's protocol (Invitrogen). Luciferase activity was determined according to standard procedures. Whole cell and nuclear extracts were prepared and subjected to immunoprecipitation and immunoblotting as in a previous study (23Bour G. Plassat J.L. Bauer A. Lalevee S. Rochette-Egly C. J. Biol. Chem. 2005; 280: 17027-17037Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar). GST Pulldown Assays-Equimolar GST or GST-SUG-1 fusion proteins produced in Escherichia coli were purified on glutathione-Sepharose 4B beads (Amersham Biosciences) and incubated with extracts from COS-1 cells overexpressing SRC-3 as described (23Bour G. Plassat J.L. Bauer A. Lalevee S. Rochette-Egly C. J. Biol. Chem. 2005; 280: 17027-17037Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar). Bound proteins were analyzed by immunoblotting. siRNA-The small interfering RNA against human and SUG-1 were from as well as the control were transfected into and cells according to the manufacturer's RNA and were and subjected to as previously described (23Bour G. Plassat J.L. Bauer A. Lalevee S. Rochette-Egly C. J. Biol. Chem. 2005; 280: 17027-17037Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar). were as human and human and cells were with RA and ChIP experiments were according to the protocol described by In were by for at in of 20 with and subjected to the ChIP The used for were as and and and of the promoters was by the from the immunoprecipitation to the from the The of the conditions was in the of antibodies and with the promoter of the control which not RA response the chromatin were as in a previous study J. R. 2004; PubMed Google Scholar), and proteins were by immunoblotting. SUG-1 with SRC-3 and to the of is degraded in cell of RA (20Gianni M. Parrella E. Raska I. Gaillard E. Nigro E.A. Gaudon C. Garattini E. Rochette-Egly C. EMBO J. 2006; 25: 739-751Crossref PubMed Scopus (72) Google Scholar). is by the proteasome and occurs through the proteasome. the ability of SUG-1, one of the six AAA ATPases of the 19 S regulatory complex of the 26 S proteasome, to interact with transcription factors (22vom Baur E. Zechel C. Heery D. Heine M.J. Garnier J.M. Vivat V. Le Douarin B. Gronemeyer H. Chambon P. Losson R. EMBO J. 1996; 15: 110-124Crossref PubMed Scopus (350) Google Scholar, Mol. 2008; PubMed Scopus Google Scholar, G. J. S. M. Oncogene. 2007; PubMed Scopus Google Scholar), we is involved in the degradation of SRC-3. we the ability of SUG-1 to interact with SRC-3 in experiments with extracts from COS-1 cells overexpressing SUG-1 and SUG-1 was by SRC-3 in the of and of RA interaction were with SRC-3 and SUG-1 proteins in cells SUG-1 interacts with SRC-3 was in in experiments using the GST-SUG-1 fusion protein interaction with the other coactivator SRC-1 not which is not degraded in response to RA (20Gianni M. Parrella E. Raska I. Gaillard E. Nigro E.A. Gaudon C. Garattini E. Rochette-Egly C. EMBO J. 2006; 25: 739-751Crossref PubMed Scopus (72) Google Scholar). Then we SUG-1 is involved in the degradation of SRC-3 by using RNA of SUG-1 in or cells with not the of SRC-3 but the degradation of the coactivator that the degradation of which also the proteasome (18Kopf E. Plassat J.L. Vivat V. de The H. Chambon P. Rochette-Egly C. J. Biol. Chem. 2000; 275: 33280-33288Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar) was not but upon of SUG-1 an of target SUG-1 and SRC-3 to the of RA that SRC-3 is a coactivator for RARα and that SUG-1 in a of transcription Mol. 2008; PubMed Scopus Google Scholar, G. J. S. M. Oncogene. 2007; PubMed Scopus Google Scholar), we SUG-1 also to the transcription of RA target genes. In RA the expression of the gene that is the of the RA target genes, as by of SUG-1 to a of the expression of of SRC-3, which not RARα or degradation of RARα also expression This that SUG-1 to transcriptional activation as as SRC-3 (20Gianni M. Parrella E. Raska I. Gaillard E. Nigro E.A. Gaudon C. Garattini E. Rochette-Egly C. EMBO J. 2006; 25: 739-751Crossref PubMed Scopus (72) Google Scholar, Chen J. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). In of the other p160 coactivators, SRC-2 and and in with the that proteins, a of in nuclear gene transcription H. X. X. B. H. D. G. Genes Dev. 2004; PubMed Scopus Google Scholar). SUG-1 and SRC-3 RARα-mediated transcription has in cells with a Luciferase reporter gene by a RA response and in cells with other RARα target genes SUG-1 with SRC-3 to the of RA we used chromatin immunoprecipitation experiments to the role by SUG-1 in the transcription of RA target genes. The gene promoter two a one and a one that to a response to RA in G.A. M. Biochem. J. 2005; PubMed Scopus Google Scholar). We the SUG-1 and SRC-3 of promoter in cells with RA a RA addition, was an of SUG-1 at the and which at and The of and to SRC-3 also with a that was with that of SUG-1 is present in the complex with SRC-3 on the cells were subjected to sequential ChIP experiments with SRC-3 and then with SUG-1 antibodies and RA addition, the and were that SUG-1 and SRC-3 a complex on DNA in an RARα was also recruited in the and in with previous D. C. V. Bauer A. de The H. Rochette-Egly C. EMBO J. PubMed Scopus Google Scholar). In experiments with RARα antibodies and then with SUG-1 was also observed at and that SUG-1 is recruited SRC-3 and RARα. This has in ChIP experiments SRC-3 RARα and SUG-1 at RA we at SUG-1 was also recruited to the promoter of other RA target genes such as the In cells and most cell the gene is by DNA M. J. M. A. M. A. B. G. C. J. 2000; PubMed Scopus Google Scholar) and is not in response to RA not However, the promoter which the is to transcription and ChIP experiments that were to those for the that SUG-1 is recruited with SRC-3 to RARα target gene the that SUG-1 is involved in transcription. that a RA was also observed and the of sequential of promoter for SUG-1 and SRC-3 R. G. Hubner M.R. G. Brand H. M. Gannon F. Cell. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). of SUG-1 of Genes and RARα analyzed the of SUG-1 on SRC-3 degradation and the transcription of RARα target genes. of SUG-1 in cells the of SRC-3 degradation the of SUG-1 in expression of SUG-1 the expression of a Luciferase reporter gene and of the target gene and also the degradation of RARα were for SUG-1, of SRC-3 or the other p160 coactivators not the transcription of RA target genes or the degradation of RARα (20Gianni M. Parrella E. Raska I. Gaillard E. Nigro E.A. Gaudon C. Garattini E. Rochette-Egly C. EMBO J. 2006; 25: 739-751Crossref PubMed Scopus (72) Google Scholar) also in cell for SUG-1, of SUG-1 to transcription and and RARα degradation and However, of SUG-1 to excess an on processes and when present in excess amounts, SUG-1 with involved in the transcription of RARα target genes and in the degradation of of SRC-3 the of SUG-1 on RARα degradation and RARα-mediated transcription. in COS-1 cells with RARα and SUG-1 expression vectors and for of SRC-3 the interaction of SUG-1 with RARα. Nuclear extracts were with RARα monoclonal antibodies and analyzed by immunoblotting. The to of and COS-1 cells were with the RARα vector and the reporter with SUG-1 and were analyzed by immunoblotting and for activity The are the of at and the as in and but with SRC-1 of SUG-1 with SRC-3 for to response to RA, SRC-3 and coregulators interact with RARα at the coactivator surface helix 12 (3Chambon P. FASEB J. 1996; 10: 940-954Crossref PubMed Scopus (2604) Google Scholar) SUG-1 interacts with RARα surface (22vom Baur E. Zechel C. Heery D. Heine M.J. Garnier J.M. Vivat V. Le Douarin B. Gronemeyer H. Chambon P. Losson R. EMBO J. 1996; 15: 110-124Crossref PubMed Scopus (350) Google Scholar) the of which is for RARα transcriptional activity and degradation (3Chambon P. FASEB J. 1996; 10: 940-954Crossref PubMed Scopus (2604) Google Scholar, 18Kopf E. Plassat J.L. Vivat V. de The H. Chambon P. Rochette-Egly C. J. Biol. Chem. 2000; 275: 33280-33288Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar). This to SUG-1 interfere with SRC-3 for RARα were with extracts from COS-1 cells with SUG-1 In the of SUG-1, an interaction between RARα and SRC-3 was in response to RA immunoprecipitation was with RARα and or antibodies and SUG-1 was interaction was and and when present in amounts, SUG-1 with the interaction between RARα and SRC-3. we of SRC-3 the excess of SUG-1 and thereby the interaction between RARα and SRC-3. We that in cells with the RARα and SUG-1 the interaction between RARα and SUG-1 was upon expression of SRC-3 the interaction between RARα and SRC-3 was RARα degradation and transcriptional which were in the of an excess of SUG-1 and were also upon of SRC-3 and and In which not interact with SUG-1, was and to the that SRC-3 the excess of SUG-1 through its ability to bind SUG-1 thereby the ability of RARα to transcription and to In gene expression in response to RA is a that is by an of dynamic and of between RARs and coregulatory proteins G. Lalevee S. Rochette-Egly C. Trends Cell Biol. 2007; 17: 302-309Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar). in response to RA, coactivators of the p160 family are recruited to cognate gene promoters by RARs through direct their nuclear receptor interaction domain and the activation through their and which as to recruit other factors that to transcriptional In addition, a variety of modifications and degradation processes with the ligand to the transcription of RA target genes (11Bastien J. Rochette-Egly C. Gene (Amst.). 2004; 328: 1-16Crossref PubMed Scopus (606) Google Scholar, 21Bour G. Lalevee S. Rochette-Egly C. Trends Cell Biol. 2007; 17: 302-309Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar). Here we identified a new mechanism underlying the activation of RARα target genes, which SUG-1, one of the ATPases of the 19 S regulatory complex of the 26 S proteasome SUG-1 with SRC-3 and to in response to RA, RARα as well as its coactivator SRC-3 are degraded by the 26 S proteasome (18Kopf E. Plassat J.L. Vivat V. de The H. Chambon P. Rochette-Egly C. J. Biol. Chem. 2000; 275: 33280-33288Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar, 20Gianni M. Parrella E. Raska I. Gaillard E. Nigro E.A. Gaudon C. Garattini E. Rochette-Egly C. EMBO J. 2006; 25: 739-751Crossref PubMed Scopus (72) Google Scholar), we SUG-1 is involved in We that SUG-1 interacts with SRC-3 in and in and to the proteasomal degradation of SRC-3. The mechanism of is but to the activity of SUG-1 such that SRC-3 degradation is G.N. Gillette T.G. Cell. 2007; 129: 659-662Abstract Full Text Full Text PDF PubMed Scopus (188) Google Scholar). However, one that SUG-1 also participates in the assembly of the 19 S and 20 S to SRC-3 to the 20 S core for degradation I. D. E. M. C. M. R.E. Mol. Cell. 2007; 25: Full Text Full Text PDF PubMed Scopus Google Scholar, H. H. H. 2001; PubMed Scopus Google Scholar). In according to SUG-1 is not for the degradation of RARα. SRC-3 is not in with was for receptor α M. Sci. S. A. 2004; PubMed Scopus Google Scholar), a of to how the proteasome is recruited for RARα SUG-1 in RA Gene present study indicates that SUG-1 also participates in the transcription of RARα target genes. to the new that dynamic of coactivators are for transcription to SUG-1 a role in the control of RARα-mediated transcription through its ability to the degradation of SRC-3. a to clear SRC-3 that other coregulators subsequently bind to the recruitment of the transcriptional G.A. Tansey W.P. Curr. Opin. Genet. Dev. 2006; 16: 197-202Crossref PubMed Scopus (213) Google Scholar, O'Malley B.W. J. Biochem. Mol. Biol. 2005; PubMed Scopus Google Scholar). However, such a model is SRC-3 degradation occurs RA when transcription has (20Gianni M. Parrella E. Raska I. Gaillard E. Nigro E.A. Gaudon C. Garattini E. Rochette-Egly C. EMBO J. 2006; 25: 739-751Crossref PubMed Scopus (72) Google Scholar). SRC-3 degradation the end of the transcriptional W.P. Genes Dev. 2001; 15: PubMed Scopus Google Scholar). In the present study evidence in SUG-1 is recruited promoters of RARα target genes. with new SUG-1 has to with promoters J.M. S. Mol. Cell. 2006; 21: Full Text Full Text PDF PubMed Scopus Google Scholar, P. S. C. 2003; PubMed Scopus Google Scholar, T.G. F. A. Sci. S. A. 2004; PubMed Scopus Google Scholar), the region promoters M. M. EMBO J. 2006; 25: PubMed Scopus Google Scholar), promoters R. G. Hubner M.R. G. Brand H. M. Gannon F. Cell. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar, H. J. Zhang Chen R. X. EMBO J. 2006; 25: PubMed Scopus (72) Google Scholar), and other promoters Mol. 2008; PubMed Scopus Google Scholar, G. J. S. M. Oncogene. 2007; PubMed Scopus Google Scholar). that SUG-1 interacts with SRC-3 and is recruited with SRC-3, one propose that SUG-1 a at RARα target genes as described for the complex D. E. B. Tansey W.P. J.L. Cell. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). it that SUG-1 is also recruited to as a of the 19 S or the of 20 and as such chromatin to recruitment of modifiers E. Tansey W.P. Mol. Cell. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar, D. S. Mol. Cell. Biol. 2008; PubMed Scopus Google Scholar). the mechanism of SUG-1 it is to that in SUG-1 has an on as a model the well which into in response to RA, we that of SUG-1 the expression of in SUG-1 RARα and RARα-mediated the present study that SUG-1 the transcription of RARα target genes as well as RARα The mechanism of is not yet but a one in which the degradation of SRC-3 observed upon SUG-1 with the of RARα-mediated such a model not with the of RARα not on SRC-3. SUG-1 interacts with transcription factors (22vom Baur E. Zechel C. Heery D. Heine M.J. Garnier J.M. Vivat V. Le Douarin B. Gronemeyer H. Chambon P. Losson R. EMBO J. 1996; 15: 110-124Crossref PubMed Scopus (350) Google Scholar, T.G. F. A. Sci. S. A. 2004; PubMed Scopus Google Scholar, G. M. J.M. 25: PubMed Scopus (72) Google Scholar), the observed a transcriptional as previously observed for other of transcriptional In of SUG-1 to interfere with SUG-1 function in protein degradation and activation of M. M. EMBO J. 2006; 25: PubMed Scopus Google Scholar), J. G. Chen J. 2004; PubMed Scopus Google Scholar), and (17Gianni M. Bauer A. Garattini E. Chambon P. Rochette-Egly C. EMBO J. 2002; 21: 3760-3769Crossref PubMed Scopus (132) Google Scholar). In SUG-1 is to interact with RARα at the surface that is for the recruitment of coactivators, the present study indicates that SUG-1 which as such to recruit the coregulators involved in transcription or in degradation the of SUG-1 by the of SRC-3, the ratio between SRC-3, and SUG-1 to crucial for the control of RARα degradation and transcriptional in with their ability to interact with In with the of the of coregulators involved in RARα-mediated we that SUG-1 between that the proteins are present with the activity at the and the the SUG-1 proteolytic to the degradation of SRC-3 and the end of the RA to the and how in the proteolytic and that SUG-1 plays a unique role in the expression of RA target genes by a between transcription and We R. Losson de de for the SUG-1 and of the cell for