Dynamic Combinatorial Networks in Nuclear Receptor-mediated Transcription

The nuclear hormone receptor (NR) 2The abbreviations used are: NR, nuclear receptor; ER, estrogen receptor; AR, androgen receptor; PR, progesterone receptor; VDR, vitamin D receptor; RAR, retinoic acid receptor; RXR, retinoic X receptor; PPAR, peroxisome proliferator activated receptor; HRE, hormone response element; N-CoR, nuclear receptor corepressor; SMRT, silencing mediator of retinoid and thyroid receptors; AF, activation function; LBD, ligand-binding domain; RNA PolII, RNA polymerase II; GTF, general transcription factor; SRC, steroid receptor coactivator; HAT, histone acetyltransferase; HMT, histone methyltransferase; CARM1, coactivator-associated arginine methyltransferase-1; PRMT1, protein arginine methyltransferase-1; CBP, cyclic AMP response element-binding protein (CREB)-binding protein; p/CAF, p300/CBP-associated factor; SWI/SNF, switch defective/sucrose nonfermenter; Cdk, cyclin-dependent kinase; ChIP, chromatin immunoprecipitation; PARP-1, poly(ADP-ribosylation) protein-1; UbcH7, ubiquitin-conjugating enzyme 7; E6-AP, papillomavirus E6-associated protein; TBL1, transducin β-like protein 1; TBLR1, TBL1-related protein; P-TEFb, positive transcription elongation factor; SUG-1 suppressor of Gal4D lesions 1; MAPK, mitogen-activated protein kinase; Erk, extracellular signal-regulated kinase; JNK, c-Jun N-terminal kinase; CAK, Cdk-activating kinase; XP, xeroderma pigmentosum; pin1, peptidyl-prolyl cis/trans isomerase; E1, ubiquitin-activating enzyme; E2, ubiquitin carrier protein; E3, ubiquitin-protein isopeptide ligase.2The abbreviations used are: NR, nuclear receptor; ER, estrogen receptor; AR, androgen receptor; PR, progesterone receptor; VDR, vitamin D receptor; RAR, retinoic acid receptor; RXR, retinoic X receptor; PPAR, peroxisome proliferator activated receptor; HRE, hormone response element; N-CoR, nuclear receptor corepressor; SMRT, silencing mediator of retinoid and thyroid receptors; AF, activation function; LBD, ligand-binding domain; RNA PolII, RNA polymerase II; GTF, general transcription factor; SRC, steroid receptor coactivator; HAT, histone acetyltransferase; HMT, histone methyltransferase; CARM1, coactivator-associated arginine methyltransferase-1; PRMT1, protein arginine methyltransferase-1; CBP, cyclic AMP response element-binding protein (CREB)-binding protein; p/CAF, p300/CBP-associated factor; SWI/SNF, switch defective/sucrose nonfermenter; Cdk, cyclin-dependent kinase; ChIP, chromatin immunoprecipitation; PARP-1, poly(ADP-ribosylation) protein-1; UbcH7, ubiquitin-conjugating enzyme 7; E6-AP, papillomavirus E6-associated protein; TBL1, transducin β-like protein 1; TBLR1, TBL1-related protein; P-TEFb, positive transcription elongation factor; SUG-1 suppressor of Gal4D lesions 1; MAPK, mitogen-activated protein kinase; Erk, extracellular signal-regulated kinase; JNK, c-Jun N-terminal kinase; CAK, Cdk-activating kinase; XP, xeroderma pigmentosum; pin1, peptidyl-prolyl cis/trans isomerase; E1, ubiquitin-activating enzyme; E2, ubiquitin carrier protein; E3, ubiquitin-protein isopeptide ligase. superfamily describes a diverse array of transcription activators working in a ligand-dependent manner and exerting action by regulating the expression of specific subsets of genes (1Laudet V. Gronemeyer H. Nuclear Receptor Factsbook. Academic Press, London2001Google Scholar, 2Gronemeyer H. Gustafsson J.A. Laudet V. Nat. Rev. Drug Discov. 2004; 3: 950-964Crossref PubMed Scopus (920) Google Scholar). The receptors for steroid hormones, which include the estrogen (ER), androgen (AR), progesterone (PR), and glucocorticoid (GR) receptors, are held in the cytoplasm, in association with chaperone complexes. Ligand binding acts as an on-switch, inducing their release from the chaperone molecules, their dimerization, their entrance into the nucleus, and their binding to hormone response elements (HREs) within the regulatory regions of target genes. In contrast, the receptors for non-steroidal hormones such as the vitamin D (VDR), retinoic acid (RARs), and peroxisome proliferator-activated (PPAR) receptors are found primarily in the nucleus and bound at HREs as heterodimers with the retinoid X receptor (RXR). They are associated with histone deacetylase-containing complexes tethered through corepressors (N-CoR and SMRT), resulting in chromatin compaction and gene silencing. Upon ligand binding, the corepressor-binding interface of NRs is destabilized, leading to the dissociation of corepressors (3Glass C.K. Rosenfeld M.G. Genes Dev. 2000; 14: 121-141Crossref PubMed Google Scholar).The basic mechanism for switching on gene transcription by liganded NRs (either steroid or non-steroid) relies on a complex and ever growing network of interactions with coregulatory proteins. For most NRs, this network is directed by a specific domain, the activation function 2 (AF-2) domain, located in the C-terminal ligand-binding domain (LBD) (Fig. 1A). The LBD is composed of 12 α helices organized as an antiparallel sandwich (Fig. 1B). Upon ligand binding, the AF-2 domain undergoes major structural rearrangements (4Chambon P. FASEB J. 1996; 10: 940-954Crossref PubMed Scopus (2587) Google Scholar, 5Renaud J.P. Moras D. Cell Mol. Life Sci. 2000; 57: 1748-1769Crossref PubMed Scopus (206) Google Scholar), creating a new binding surface for coactivators (Fig. 1B). The AF-2 domain cooperates with a second activation domain residing in the N terminus, the AF-1 domain (4Chambon P. FASEB J. 1996; 10: 940-954Crossref PubMed Scopus (2587) Google Scholar), to recruit multiple complexes to alter the chromatin structure surrounding the promoter of target genes (6Cosma M.P. Mol. Cell. 2002; 10: 227-236Abstract Full Text Full Text PubMed Scopus Google Scholar, Cell. 2002; Full Text Full Text PubMed Scopus Google Scholar, P. PubMed Scopus Google Scholar). In the the for the of the transcription RNA polymerase and the general transcription Nat. Mol. 2004; PubMed Scopus Google the is NRs and their are to and in a and the of complexes and a and and of NRs, and the In this on the of the interactions NRs and their and on their by a of or in response to the ligand or to in the the are with the at the and at the of NRs and at a the hormone NRs bound at HREs an and of a of complexes. major of coactivators of the by and J. Mol. PubMed Scopus Google Scholar), which as histone such as and Cell Mol. Life Sci. PubMed Scopus Google Scholar), histone arginine such as or Rev. PubMed Scopus Google Scholar), complexes such as Cell. 2002; Full Text Full Text PubMed Scopus Google Scholar, M.G. Cell. Full Text Full Text PubMed Scopus Google Scholar), and the mediator complex D. J. Cell. Sci. PubMed Scopus Google Scholar, Nat. Rev. Mol. Cell. 2004; PubMed Scopus Google acts as a NRs and the and of coactivators with In chromatin H. Cell. Full Text Full Text PubMed Scopus Google the of a this and the of coactivators are the to to the by the and in with their in the of the complexes in chromatin the mediator is the of RNA and the of of complexes from target gene to the 2004; PubMed Scopus Google Scholar), a multiple for gene activation on promoter an a the mediator and RNA at the promoter of the gene is in the is by a PARP-1, which the mediator to an through the release of the and the of H. P. P. D. Mol. Cell. Full Text Full Text PubMed Scopus Google Scholar).The a of the through the of the of the of the of NRs and their at a the for the and a new in and is steroid receptors, with their on and the promoter with response elements H. Cell. Full Text Full Text PubMed Scopus Google Scholar, H. D. J. J. Mol. Cell. Full Text Full Text PubMed Scopus Google Scholar, J. 2002; Full Text Full Text PubMed Scopus Google Scholar, Mol. Cell. 2004; 14: Full Text Full Text PubMed Scopus Google Scholar). the cyclic with transcription complexes a of activated by this cyclic of NRs and their on a target promoter directed by cyclic in chromatin structure and in the of NRs, and their on within of the transcription their H. D. J. J. Mol. Cell. Full Text Full Text PubMed Scopus Google Scholar, J. H. 2002; PubMed Scopus Google Scholar, Mol. Cell. 2004; PubMed Scopus Google Scholar). this is by the the regulatory for Nat. Rev. Mol. Cell. PubMed Scopus Google Scholar, Rev. PubMed Scopus Google and is in the which of an ubiquitin-activating ubiquitin-conjugating and multiple ubiquitin ubiquitin to target and the which a complex and a complex the and for into the NRs, as as and of the are and by the in response to the ligand Mol. 2004; PubMed Scopus Google Scholar, V. The H. P. J. 2000; Full Text Full Text PubMed Scopus Google Scholar, Sci. Full Text Full Text PubMed Scopus Google Scholar, J. Mol. PubMed Scopus Google Scholar). the of this is to an mechanism for of the Genes Dev. PubMed Scopus Google Scholar, D. 2000; 10: Full Text Full Text PubMed Scopus Google in a on the is to the by the an mechanism for regulating the cyclic of NRs with the promoter H. D. J. J. Mol. Cell. Full Text Full Text PubMed Scopus Google Scholar, Mol. Cell. 2004; PubMed Scopus Google Scholar). the most mechanism to corepressors coactivators J. Mol. PubMed Scopus Google Scholar). In with this ubiquitin-conjugating and ubiquitin to with NRs and their coactivators and to in transcription as as in the of the J. Mol. PubMed Scopus Google Scholar). V. C.K. Rosenfeld M.G. Cell. 2004; Full Text Full Text PubMed Scopus Google and TBLR1, which are of ubiquitin function as for the of the and the of the a the of for complexes. of NRs and their of the the to a elongation complex Cell. Full Text Full Text PubMed Scopus Google Scholar, Cell. Full Text Full Text PubMed Scopus Google Scholar). the with polymerase complexes and is for complexes at Sci. 2004; PubMed Scopus Google Scholar). are with the transcription is a with and of NRs, and of the for and the of transcription and the is the is in the function in activation of Nat. Rev. Mol. Cell. PubMed Scopus Google Scholar, 2002; PubMed Scopus Google Scholar). In with ubiquitin are of the complexes and of the RNA transcription 2002; PubMed Scopus Google and in transcription In the of transcription elongation by the of the elongation by transcription activators 2004; 14: Full Text Full Text PubMed Scopus Google Scholar). is the which is of the of the regulatory complex of the as with NRs, the general transcription and RNA and is to genes 2002; PubMed Scopus Google Scholar, P. J. 2002; PubMed Scopus Google Scholar). the complex transcription and elongation by protein complexes chromatin through chaperone 2002; PubMed Scopus Google Scholar, Mol. Cell. Full Text Full Text PubMed Scopus Google Scholar, P. PubMed Scopus Google Scholar). of the complex to the interactions from and to the of the complexes. an mechanism from the are Genes Dev. 2004; PubMed Scopus Google Scholar). In with the histone new for binding chromatin and such as and Mol. Cell. PubMed Scopus Google Scholar). is histone a structural by the Mol. Cell. 2004; Full Text Full Text PubMed Scopus Google is of the function to the of transcription in diverse from the of chromatin to the of the complexes. to the growing of with in the transcription and new regulatory in the to NRs and a of the of transcription by NRs Cell. PubMed Scopus Google Scholar). of steroid and hormones are to with through the activation of an and retinoic acid to the activation of and which the nucleus and the N-terminal AF-1 of and P. J. 2002; PubMed Scopus Google Scholar, Cell. PubMed Scopus Google Scholar, PubMed Scopus Google (Fig. is a in the of transcription PubMed Scopus Google Scholar). In of the AF-1 domain of NRs the of the of chromatin Cell. PubMed Scopus Google Scholar). the dissociation of proteins. In with J. Full Text Full Text PubMed Scopus Google of the AF-1 domain of the the dissociation of a of such a dissociation is by the of in to transcription to by the and the of NRs such as P. J. 2002; PubMed Scopus Google and Mol. Cell. PubMed Scopus Google Scholar). the transcription and are of ubiquitin which on the transcription by NRs to the transcription on the Nat. Rev. Mol. Cell. PubMed Scopus Google Scholar, 2002; PubMed Scopus Google Scholar, J. 2004; PubMed Scopus Google Scholar). to the AF-1 of NRs recruit complexes with ubiquitin as by this with the corepressors and coactivators are by in response to and non-steroidal hormones C.K. Rosenfeld M.G. 2002; Full Text Full Text PubMed Scopus Google Scholar, J. 2004; Full Text Full Text PubMed Scopus Google Scholar, Rev. PubMed Scopus Google Scholar). In with the transcription of the corepressors a for their and to the of coactivators V. C.K. Rosenfeld M.G. Cell. 2004; Full Text Full Text PubMed Scopus Google Scholar). The coactivators are The is which at by in response to Rev. PubMed Scopus Google and retinoic acid and for and Rev. PubMed Scopus Google the for a the of to a for found to by PubMed Scopus Google Scholar, Nat. Rev. Mol. Cell. 2002; 3: PubMed Scopus Google Scholar). to the histone a and with and to for the of chromatin or is the of transcription through the and of NRs and their within of and new the is NRs are by the of which is a general transcription composed of J.A. D. Nat. 2004; PubMed Scopus Google Scholar). by in the of P. Cell. Full Text Full Text PubMed Scopus Google Scholar, J. P. J. 2000; Full Text Full Text PubMed Scopus Google Scholar), NRs D. Mol. Cell. 2000; Full Text Full Text PubMed Scopus Google Scholar), J. 2000; Full Text Full Text PubMed Scopus Google Scholar), and P. Mol. Cell. 14: Scopus Google Scholar), to by The of in from in the of in of the to in NRs are and the ligand-dependent response is P. Mol. Cell. 14: Scopus Google Scholar, Cell. 2002; Full Text Full Text PubMed Scopus Google Scholar, P. P. P. Mol. Cell. 2004; Full Text Full Text PubMed Scopus Google Scholar). expression of at in a the of and activation of target genes in response to retinoic acid M.P. P. J. PubMed Scopus Google is to the promoter in with the and the coactivators and the chromatin complexes H. Cell. Full Text Full Text PubMed Scopus Google Scholar, H. P. P. D. Mol. Cell. Full Text Full Text PubMed Scopus Google Scholar). to the promoter to NRs bound at their HRE, through specific J. P. J. 2000; Full Text Full Text PubMed Scopus Google Scholar, D. Mol. Cell. 2000; Full Text Full Text PubMed Scopus Google Scholar), the by the of the located in a within the N-terminal AF-1 domain of NRs (Fig. 1A). In an on the and NRs, P. P. P. Mol. Cell. 2004; Full Text Full Text PubMed Scopus Google in the of a AF-1 domain, as for VDR, a second by with VDR, the of an AF-1 for NRs such as the by is to the (Fig. in the and for the activation of target a new of through J. 2004; PubMed Scopus Google by a the of in of the the of the to to a to for of the RNA by the within Nat. Mol. 2004; PubMed Scopus Google Scholar). a include of the the Nat. 10: PubMed Scopus Google Scholar). In with this the to the of V. PubMed Scopus Google Scholar). to the the and of the as is a specific for an Nat. 10: PubMed Scopus Google in to a to the Ligand new for in of transcription are at an extracellular such as or at protein or cyclic protein which the nucleus and In in response to such is of the of which is in response to to by such as the of the ligand-binding through the AF-1 domain and the ligand-binding D. PubMed Scopus Google or the of the receptor by the P. J. 2000; Full Text Full Text PubMed Scopus Google Scholar). 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The of coactivators is and as as HAT, HMT, and ubiquitin complexes. are and and for the of complexes such as complexes. In their the coactivators are by the ubiquitin to their by the with the of the coactivators with an function in chromatin leading to the of within the promoter and the of RNA and this to with NRs, and the their AF-1 in the of the complex In the complex and RNA from the promoter with of ubiquitin and chromatin to in NRs are by the to this transcription of of the histone deacetylase-containing complexes are and chromatin is The nuclear hormone receptor (NR) 2The abbreviations used are: NR, nuclear receptor; ER, estrogen receptor; AR, androgen receptor; PR, progesterone receptor; VDR, vitamin D receptor; RAR, retinoic acid receptor; RXR, retinoic X receptor; PPAR, peroxisome proliferator activated receptor; HRE, hormone response element; N-CoR, nuclear receptor corepressor; SMRT, silencing mediator of retinoid and thyroid receptors; AF, activation function; LBD, ligand-binding domain; RNA PolII, RNA polymerase II; GTF, general transcription factor; SRC, steroid receptor coactivator; HAT, histone acetyltransferase; HMT, histone methyltransferase; CARM1, coactivator-associated arginine methyltransferase-1; PRMT1, protein arginine methyltransferase-1; CBP, cyclic AMP response element-binding protein (CREB)-binding protein; p/CAF, p300/CBP-associated factor; SWI/SNF, switch defective/sucrose nonfermenter; Cdk, cyclin-dependent kinase; ChIP, chromatin immunoprecipitation; PARP-1, poly(ADP-ribosylation) protein-1; UbcH7, ubiquitin-conjugating enzyme 7; E6-AP, papillomavirus E6-associated protein; TBL1, transducin β-like protein 1; TBLR1, TBL1-related protein; P-TEFb, positive transcription elongation factor; SUG-1 suppressor of Gal4D lesions 1; MAPK, mitogen-activated protein kinase; Erk, extracellular signal-regulated kinase; JNK, c-Jun N-terminal kinase; CAK, Cdk-activating kinase; XP, xeroderma pigmentosum; pin1, peptidyl-prolyl cis/trans isomerase; E1, ubiquitin-activating enzyme; E2, ubiquitin carrier protein; E3, ubiquitin-protein isopeptide ligase.2The abbreviations used are: NR, nuclear receptor; ER, estrogen receptor; AR, androgen receptor; PR, progesterone receptor; VDR, vitamin D receptor; RAR, retinoic acid receptor; RXR, retinoic X receptor; PPAR, peroxisome proliferator activated receptor; HRE, hormone response element; N-CoR, nuclear receptor corepressor; SMRT, silencing mediator of retinoid and thyroid receptors; AF, activation function; LBD, ligand-binding domain; RNA PolII, RNA polymerase II; GTF, general transcription factor; SRC, steroid receptor coactivator; HAT, histone acetyltransferase; HMT, histone methyltransferase; CARM1, coactivator-associated arginine methyltransferase-1; PRMT1, protein arginine methyltransferase-1; CBP, cyclic AMP response element-binding protein (CREB)-binding protein; p/CAF, p300/CBP-associated factor; SWI/SNF, switch defective/sucrose nonfermenter; Cdk, cyclin-dependent kinase; ChIP, chromatin immunoprecipitation; PARP-1, poly(ADP-ribosylation) protein-1; UbcH7, ubiquitin-conjugating enzyme 7; E6-AP, papillomavirus E6-associated protein; TBL1, transducin β-like protein 1; TBLR1, TBL1-related protein; P-TEFb, positive transcription elongation factor; SUG-1 suppressor of Gal4D lesions 1; MAPK, mitogen-activated protein kinase; Erk, extracellular signal-regulated kinase; JNK, c-Jun N-terminal kinase; CAK, Cdk-activating kinase; XP, xeroderma pigmentosum; pin1, peptidyl-prolyl cis/trans isomerase; E1, ubiquitin-activating enzyme; E2, ubiquitin carrier protein; E3, ubiquitin-protein isopeptide ligase. superfamily describes a diverse array of transcription activators working in a ligand-dependent manner and exerting action by regulating the expression of specific subsets of genes (1Laudet V. Gronemeyer H. Nuclear Receptor Factsbook. Academic Press, London2001Google Scholar, 2Gronemeyer H. Gustafsson J.A. Laudet V. Nat. Rev. Drug Discov. 2004; 3: 950-964Crossref PubMed Scopus (920) Google Scholar). The receptors for steroid hormones, which include the estrogen (ER), androgen (AR), progesterone (PR), and glucocorticoid (GR) receptors, are held in the cytoplasm, in association with chaperone complexes. Ligand binding acts as an on-switch, inducing their release from the chaperone molecules, their dimerization, their entrance into the nucleus, and their binding to hormone response elements (HREs) within the regulatory regions of target genes. In contrast, the receptors for non-steroidal hormones such as the vitamin D (VDR), retinoic acid (RARs), and peroxisome proliferator-activated (PPAR) receptors are found primarily in the nucleus and bound at HREs as heterodimers with the retinoid X receptor (RXR). They are associated with histone deacetylase-containing complexes tethered through corepressors (N-CoR and SMRT), resulting in chromatin compaction and gene silencing. Upon ligand binding, the corepressor-binding interface of NRs is destabilized, leading to the dissociation of corepressors (3Glass C.K. Rosenfeld M.G. Genes Dev. 2000; 14: 121-141Crossref PubMed Google Scholar). The basic mechanism for switching on gene transcription by liganded NRs (either steroid or non-steroid) relies on a complex and ever growing network of interactions with coregulatory proteins. For most NRs, this network is directed by a specific domain, the activation function 2 (AF-2) domain, located in the C-terminal ligand-binding domain (LBD) (Fig. 1A). The LBD is composed of 12 α helices organized as an antiparallel sandwich (Fig. 1B). Upon ligand binding, the AF-2 domain undergoes major structural rearrangements (4Chambon P. FASEB J. 1996; 10: 940-954Crossref PubMed Scopus (2587) Google Scholar, 5Renaud J.P. Moras D. Cell Mol. Life Sci. 2000; 57: 1748-1769Crossref PubMed Scopus (206) Google Scholar), creating a new binding surface for coactivators (Fig. 1B). The AF-2 domain cooperates with a second activation domain residing in the N terminus, the AF-1 domain (4Chambon P. FASEB J. 1996; 10: 940-954Crossref PubMed Scopus (2587) Google Scholar), to recruit multiple complexes to alter the chromatin structure surrounding the promoter of target genes (6Cosma M.P. Mol. Cell. 2002; 10: 227-236Abstract Full Text Full Text PubMed Scopus Google Scholar, Cell. 2002; Full Text Full Text PubMed Scopus Google Scholar, P. PubMed Scopus Google Scholar). In the the for the of the transcription RNA polymerase and the general transcription Nat. Mol. 2004; PubMed Scopus Google Scholar). the is NRs and their are to and in a and the of complexes and a and and of NRs, and the In this on the of the interactions NRs and their and on their by a of or in response to the ligand or to in the the are with the at the and at the of NRs and at a the hormone NRs bound at HREs an and of a of complexes. major of coactivators of the by and J. Mol. PubMed Scopus Google Scholar), which as histone such as and Cell Mol. Life Sci. PubMed Scopus Google Scholar), histone arginine such as or Rev. PubMed Scopus Google Scholar), complexes such as Cell. 2002; Full Text Full Text PubMed Scopus Google Scholar, M.G. Cell. Full Text Full Text PubMed Scopus Google Scholar), and the mediator complex D. J. Cell. Sci. PubMed Scopus Google Scholar, Nat. Rev. Mol. Cell. 2004; PubMed Scopus Google acts as a NRs and the and of coactivators with In chromatin H. Cell. Full Text Full Text PubMed Scopus Google the of a this and the of coactivators are the to to the by the and in with their in the of the complexes in chromatin the mediator is the of RNA and the of of complexes from target gene to the 2004; PubMed Scopus Google Scholar), a multiple for gene activation on promoter an a the mediator and RNA at the promoter of the gene is in the is by a PARP-1, which the mediator to an through the release of the and the of H. P. P. D. Mol. Cell. Full Text Full Text PubMed Scopus Google Scholar). the hormone NRs bound at HREs an and of a of complexes. major of coactivators of the by and J. Mol. PubMed Scopus Google Scholar), which as histone such as and Cell Mol. Life Sci. PubMed Scopus Google Scholar), histone arginine such as or Rev. PubMed Scopus Google Scholar), complexes such as Cell. 2002; Full Text Full Text PubMed Scopus Google Scholar, M.G. Cell. Full Text Full Text PubMed Scopus Google Scholar), and the mediator complex D. J. Cell. Sci. PubMed Scopus Google Scholar, Nat. Rev. Mol. Cell. 2004; PubMed Scopus Google acts as a NRs and the The and of coactivators with In chromatin H. Cell. Full Text Full Text PubMed Scopus Google the of a this and the of coactivators are the to to the by the and in with their in the of the complexes in chromatin the mediator is the of RNA and the of of complexes from target gene to the 2004; PubMed Scopus Google Scholar), a multiple for gene activation on promoter an a the mediator and RNA at the promoter of the gene is in the is by a PARP-1, which the mediator to an through the release of the and the of H. P. P. D. Mol. Cell. Full Text Full Text PubMed Scopus Google Scholar). The a of the through the of the of the of the of NRs and their at a the for the and a new in and is steroid receptors, with their on and the promoter with response elements H. Cell. Full Text Full Text PubMed Scopus Google Scholar, H. D. J. J. Mol. Cell. Full Text Full Text PubMed Scopus Google Scholar, J. 2002; Full Text Full Text PubMed Scopus Google Scholar, Mol. Cell. 2004; 14: Full Text Full Text PubMed Scopus Google Scholar). the cyclic with transcription complexes a of activated by this cyclic of NRs and their on a target promoter directed by cyclic in chromatin structure and in the of NRs, and their on within of the transcription their H. D. J. J. Mol. Cell. Full Text Full Text PubMed Scopus Google Scholar, J. H. 2002; PubMed Scopus Google Scholar, Mol. Cell. 2004; PubMed Scopus Google Scholar). this is by the the regulatory for Nat. Rev. Mol. Cell. PubMed Scopus Google Scholar, Rev. PubMed Scopus Google and is in the which of an ubiquitin-activating ubiquitin-conjugating and multiple ubiquitin ubiquitin to target and the which a complex and a complex the and for into the NRs, as as and of the are and by the in response to the ligand Mol. 2004; PubMed Scopus Google Scholar, V. The H. P. J. 2000; Full Text Full Text PubMed Scopus Google Scholar, Sci. Full Text Full Text PubMed Scopus Google Scholar, J. Mol. PubMed Scopus Google Scholar). the of this is to an mechanism for of the Genes Dev. PubMed Scopus Google Scholar, D. 2000; 10: Full Text Full Text PubMed Scopus Google in a on the is to the by the an mechanism for regulating the cyclic of NRs with the promoter H. D. J. J. Mol. Cell. Full Text Full Text PubMed Scopus Google Scholar, Mol. Cell. 2004; PubMed Scopus Google Scholar). the most mechanism to corepressors coactivators J. Mol. PubMed Scopus Google Scholar). In with this ubiquitin-conjugating and ubiquitin to with NRs and their coactivators and to in transcription as as in the of the J. Mol. PubMed Scopus Google Scholar). V. C.K. Rosenfeld M.G. Cell. 2004; Full Text Full Text PubMed Scopus Google and TBLR1, which are of ubiquitin function as for the of the and the of the a the of for complexes. of NRs and their of the the to a elongation complex Cell. Full Text Full Text PubMed Scopus Google Scholar, Cell. Full Text Full Text PubMed Scopus Google Scholar). the with polymerase complexes and is for complexes at Sci. 2004; PubMed Scopus Google Scholar). are with the transcription is a with and of NRs, and of the the of the of the of the of NRs and their at a the for the and a new in and is steroid receptors, with their on and the promoter with response elements H. Cell. Full Text Full Text PubMed Scopus Google Scholar, H. D. J. J. Mol. Cell. Full Text Full Text PubMed Scopus Google Scholar, J. 2002; Full Text Full Text PubMed Scopus Google Scholar, Mol. Cell. 2004; 14: Full Text Full Text PubMed Scopus Google Scholar). the cyclic with transcription complexes a of activated by this cyclic of NRs and their on a target promoter directed by cyclic in chromatin structure and in the of NRs, and their on within of the transcription their H. D. J. J. Mol. Cell. Full Text Full Text PubMed Scopus Google Scholar, J. H. 2002; PubMed Scopus Google Scholar, Mol. Cell. 2004; PubMed Scopus Google Scholar). this is by the the regulatory for Nat. Rev. Mol. Cell. PubMed Scopus Google Scholar, Rev. PubMed Scopus Google and is in the which of an ubiquitin-activating ubiquitin-conjugating and multiple ubiquitin ubiquitin to target and the which a complex and a complex the and for into the NRs, as as and of the are and by the in response to the ligand Mol. 2004; PubMed Scopus Google Scholar, V. The H. P. J. 2000; Full Text Full Text PubMed Scopus Google Scholar, Sci. Full Text Full Text PubMed Scopus Google Scholar, J. Mol. PubMed Scopus Google Scholar). the of this is to an mechanism for of the Genes Dev. PubMed Scopus Google Scholar, D. 2000; 10: Full Text Full Text PubMed Scopus Google Scholar). in a on the is to the by the an mechanism for regulating the cyclic of NRs with the promoter H. D. J. J. Mol. Cell. Full Text Full Text PubMed Scopus Google Scholar, Mol. Cell. 2004; PubMed Scopus Google Scholar). the most mechanism to corepressors coactivators J. Mol. PubMed Scopus Google Scholar). In with