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• W2021082813 abstract "The orphan nuclear receptor small heterodimer partner (SHP; NR0B2) interacts with a wide array of nuclear receptors and represses their transcriptional activity. SHP expression is regulated by several other members of the nuclear receptor superfamily, including the orphan receptors SF-1 and LRH-1, and the bile acid receptor FXR. We have found that the SHP promoter is also activated by the estrogen receptor-related receptor γ (ERRγ) but not the related ERRα and ERRβ isoforms. SHP and ERRγ mRNAs are coexpressed in several tissues, including pancreas, kidney, and heart, confirming the potential relevance of this transactivation. ERRγ transactivation is dependent on only one of five previously characterized DNA-binding sites for SF-1, and this element differs from previously reported ERR response elements. However, treatment with the histone deacetylase inhibitor trichostatin A significantly increased ERRα and ERRβ activity on this element indicating that the lack of activity of ERRα and -β may depend on their association with co-repressor in vivo. Furthermore, using protease sensitivity assays on DNA bound receptors it was demonstrated that DNA sequence of different response elements may cause allosteric modulation of ERR proteins, which in turn may be responsible for the differential activities of these receptors on different response elements. SHP inhibits ERRγ transactivation and physically interacts with all three members of ERR subfamily, as demonstrated by both yeast two-hybrid and biochemical assays. As with other SHP targets, this interaction is dependent on the AF-2 coactivator-binding site of ERRγ and the previously described N-terminal receptor interaction domain of SHP. Several recently described SHP mutations associated with moderate obesity in humans block the inhibition of ERRγ activity. Overall, these results identify a new autoregulatory loop controlling SHP gene expression and significantly extend the potential functional roles of the three ERRs. The orphan nuclear receptor small heterodimer partner (SHP; NR0B2) interacts with a wide array of nuclear receptors and represses their transcriptional activity. SHP expression is regulated by several other members of the nuclear receptor superfamily, including the orphan receptors SF-1 and LRH-1, and the bile acid receptor FXR. We have found that the SHP promoter is also activated by the estrogen receptor-related receptor γ (ERRγ) but not the related ERRα and ERRβ isoforms. SHP and ERRγ mRNAs are coexpressed in several tissues, including pancreas, kidney, and heart, confirming the potential relevance of this transactivation. ERRγ transactivation is dependent on only one of five previously characterized DNA-binding sites for SF-1, and this element differs from previously reported ERR response elements. However, treatment with the histone deacetylase inhibitor trichostatin A significantly increased ERRα and ERRβ activity on this element indicating that the lack of activity of ERRα and -β may depend on their association with co-repressor in vivo. Furthermore, using protease sensitivity assays on DNA bound receptors it was demonstrated that DNA sequence of different response elements may cause allosteric modulation of ERR proteins, which in turn may be responsible for the differential activities of these receptors on different response elements. SHP inhibits ERRγ transactivation and physically interacts with all three members of ERR subfamily, as demonstrated by both yeast two-hybrid and biochemical assays. As with other SHP targets, this interaction is dependent on the AF-2 coactivator-binding site of ERRγ and the previously described N-terminal receptor interaction domain of SHP. Several recently described SHP mutations associated with moderate obesity in humans block the inhibition of ERRγ activity. Overall, these results identify a new autoregulatory loop controlling SHP gene expression and significantly extend the potential functional roles of the three ERRs. DNA-binding domain small heterodimer partner estrogen receptor-related receptor thyroid hormone receptor, GR, glucocorticoid receptor ERR response element steroidogenic factor 1 liver receptor homolog 1 SF-1 response element estrogen response element palindromic thyroid hormone response element glucocorticoid receptor interacting protein 1 trichostatin A ligand-binding domain estrogen receptor glutathione S-transferase hemagglutinin The nuclear receptor superfamily is a diverse group of transcription factors that includes both conventional receptors with known ligands and orphan nuclear receptors that lack them (for reviews, see Refs. 1Evans R.M. Science. 1988; 240: 889-895Crossref PubMed Scopus (6292) Google Scholar and 2Giguere V. Endocr. Rev. 1999; 20: 689-725Crossref PubMed Scopus (707) Google Scholar). Both conventional and orphan nuclear receptors share a very similar structure. At the N terminus is a domain that is not conserved in sequence in different receptor families, but in many cases contains a ligand independent transcriptional activation domain termed activation function 1. The central DNA-binding domain (DBD)1 is strongly conserved and includes two zinc-binding units based on invariant cysteine residues. A conserved helical region within the DBD termed the P box (3Umesono K. Evans R.M. Cell. 1989; 57: 1139-1146Abstract Full Text PDF PubMed Scopus (720) Google Scholar) makes base specific contacts with hormone response elements. The sequence of this motif serves as one of the main criteria for dividing the nuclear receptor superfamily into subgroups. The C-terminal ligand-binding domain (LBD) functions not only in ligand binding, but also dimerization and ligand mediated transcriptional activation. This transactivation is based on an additional activation function referred to as AF-2. In most receptors, allosteric effects of ligand binding result in the formation of an appropriate binding site for a series of transcriptional coactivators. In a number of orphans, however, coactivator binding is not dependent on the presence of a ligand. Members of this subset of orphans, which includes HNF-4, and ERRγ, function as constitutive transactivators (4Hadzopoulou-Cladaras M. Kistanova E. Evagelopoulou C. Zeng S. Cladaras C. Ladias J.A. J. Biol. Chem. 1997; 272: 539-550Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar, 5Hong H. Yang L. Stallcup M.R. J. Biol. Chem. 1999; 274: 22618-22626Abstract Full Text Full Text PDF PubMed Scopus (256) Google Scholar).SHP is an atypical member of nuclear receptor superfamily that lacks a DBD. Various studies have reported SHP to be a repressor of transcriptional activities of a number of nuclear receptors, including both ligand responsive receptors like, ER, TR, RAR, and RXR, and orphan receptors like CAR, HNF-4, and FTF (6Johansson L. Thomsen J.S. Damdimopoulos A.E. Spyrou G. Gustafsson J.A. Treuter E. J. Biol. Chem. 1999; 274: 345-353Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar, 7Lee Y.K. Dell H. Dowhan D.H. Hadzopoulou-Cladaras M. Moore D.D. Mol. Cell. Biol. 2000; 20: 187-195Crossref PubMed Scopus (263) Google Scholar, 8Seol W. Choi H.S. Moore D.D. Science. 1996; 272: 1336-1339Crossref PubMed Scopus (438) Google Scholar, 9Seol W. Chung M. Moore D.D. Mol. Cell. Biol. 1997; 17: 7126-7131Crossref PubMed Scopus (118) Google Scholar, 10Seol W. Hanstein B. Brown M. Moore D.D. Mol. Endocrinol. 1998; 10: 1551-1557Crossref Scopus (126) Google Scholar). The very broad range of receptors sensitive to inhibition by SHP suggests a central role for SHP in modulation of nuclear receptor signaling pathways. Although the mechanisms underlying this repressive function remain unclear, recent results (7Lee Y.K. Dell H. Dowhan D.H. Hadzopoulou-Cladaras M. Moore D.D. Mol. Cell. Biol. 2000; 20: 187-195Crossref PubMed Scopus (263) Google Scholar, 11Johansson L. Bavner A. Thomsen J.S. Farnegardh M. Gustafsson J.A. Treuter E. Mol. Cell. Biol. 2000; 20: 1124-1133Crossref PubMed Scopus (132) Google Scholar) demonstrate that SHP can compete with coactivators for binding to the AF-2 surface. In addition, a direct transcriptional repressor domain contributes significantly to the inhibitory function of SHP.The SHP gene is structurally conserved in all the species from which it has been characterized. It consists of 2 exons interrupted by an intron and is located on human chromosome 1 at position 1p36.1 (12Lee H.K. Lee Y.K. Park S.H. Kim Y.S. Park S.H. Lee J.W. Kwon H.B. Soh J. Moore D.D. Choi H.S. J. Biol. Chem. 1998; 273: 14398-14440Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar). Initial studies indicated that SHP is expressed predominantly in the liver, spleen, small intestine, and pancreas (8Seol W. Choi H.S. Moore D.D. Science. 1996; 272: 1336-1339Crossref PubMed Scopus (438) Google Scholar,12Lee H.K. Lee Y.K. Park S.H. Kim Y.S. Park S.H. Lee J.W. Kwon H.B. Soh J. Moore D.D. Choi H.S. J. Biol. Chem. 1998; 273: 14398-14440Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar). However, later studies with more sensitive approaches have demonstrated the presence of SHP mRNA in a wide variety of tissues, with highest expression in heart, brain, liver, lung, and adrenal gland (11Johansson L. Bavner A. Thomsen J.S. Farnegardh M. Gustafsson J.A. Treuter E. Mol. Cell. Biol. 2000; 20: 1124-1133Crossref PubMed Scopus (132) Google Scholar). Although very little is known about SHP gene regulation, some recent reports have suggested important roles for the bile acid receptor FXR, and AP-1 transcription factors in regulatingSHP gene expression and subsequent regulation of cholesterol homeostasis (13Goodwin B. Jones S.A. Price R.R. Watson M.A. McKee D.D. Moore L.B. Galardi C. Wilson J.G. Lewis M.C. Roth M.E. Maloney P.R. Willson T.M. Kliewer S.A. Mol. Cell. Biol. 2000; 5: 517-526Google Scholar, 14Lu T.T. Makishima M. Repa J.J. Schoonjans K. Kerr T.A. Auwerx J. Mangelsdorf D.J. Mol. Cell. 2000; 6: 507-515Abstract Full Text Full Text PDF PubMed Scopus (1208) Google Scholar, 15Gupta S. Stravitz R.T. Dent P. Hyelmon P.B. J. Biol. Chem. 2001; 276: 15816-15822Abstract Full Text Full Text PDF PubMed Scopus (274) Google Scholar). A recent report also demonstrated the activation of the SHP promoter by SF-1 and its close relative LRH-1, both of which bind five distinct sites present in the region spanning from 453 to 68 base pairs upstream of the transcriptional start (16Lee Y.K. Parker K.L. Choi H.S. Moore D.D. J. Biol. Chem. 1999; 274: 20869-20873Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar). SHP is coexpressed with SF-1 or LRH-1 only in gonads, adrenal gland, and liver, however, indicating that other transcription factors are involved in SHP gene expression in other tissues, such as pancreas, heart, and brain.The ERR subfamily includes the first orphan receptors described (17Giguere V. Yang N. Segui P. Evans R.M. Nature. 1988; 331: 91-94Crossref PubMed Scopus (690) Google Scholar). These proteins form a distinct subgroup within the superfamily with striking sequence similarity in the DBD with estrogen receptors (ER). The similarity in the LBD is more limited, and the ERRs do not bind natural estrogen. However, a recent report has demonstrated the binding of the synthetic estrogen analogue diethylstilbestrol to the ERR subfamily members (18Tremblay G.B. Kunath T. Bergeron D. Lapointe L. Champigny C. Bader Jo-Ann Rossant J. Giguère V. Genes Dev. 2001; 15: 833-838Crossref PubMed Scopus (233) Google Scholar). In this case, diethylstilbestrol acts as an inverse agonist by disrupting ERR-coactivator interaction (18Tremblay G.B. Kunath T. Bergeron D. Lapointe L. Champigny C. Bader Jo-Ann Rossant J. Giguère V. Genes Dev. 2001; 15: 833-838Crossref PubMed Scopus (233) Google Scholar). Three different ERR genes have been characterized (5Hong H. Yang L. Stallcup M.R. J. Biol. Chem. 1999; 274: 22618-22626Abstract Full Text Full Text PDF PubMed Scopus (256) Google Scholar, 17Giguere V. Yang N. Segui P. Evans R.M. Nature. 1988; 331: 91-94Crossref PubMed Scopus (690) Google Scholar, 19Eudy J.D. Yao S. Weston M.D. Ma-Edmonds M. Talmadge C.B. Cheng J.J. Kimberling W.J. Sumegi J. Genomics. 1998; 50: 382-384Crossref PubMed Scopus (119) Google Scholar, 20Heard D.J. Norby P.L. Hollowa Y.J. Vissing H. Mol. Endocrinol. 2000; 14: 382-392Crossref PubMed Scopus (191) Google Scholar). The ERRα, ERRβ, and ERRγ isoforms show considerable homology among themselves, with the highest similarity between ERRβ and ERRγ. The hypervariable N-terminal A/B domain of ERRβ shares 58.2% amino acid identity with ERRγ, and in the DBD and the LBD they share 98.9 and 73.1% identity, respectively (5Hong H. Yang L. Stallcup M.R. J. Biol. Chem. 1999; 274: 22618-22626Abstract Full Text Full Text PDF PubMed Scopus (256) Google Scholar). All three isoforms have been reported to bind and transactivate both estrogen response elements (ERE) and SF-1 response elements (SF-1RE) (5Hong H. Yang L. Stallcup M.R. J. Biol. Chem. 1999; 274: 22618-22626Abstract Full Text Full Text PDF PubMed Scopus (256) Google Scholar, 20Heard D.J. Norby P.L. Hollowa Y.J. Vissing H. Mol. Endocrinol. 2000; 14: 382-392Crossref PubMed Scopus (191) Google Scholar, 21Bonnelye E. Vanacker J.M. Dittmar T. Begue A. Desbiens X. Denhardt D.T. Aubin J.E. Laudet V. Fournier B. Mol. Endocrinol. 1997; 7: 905-916Crossref Scopus (130) Google Scholar, 22Johnston S.D. Liu X. Zuo F. Eisenbraun T.L. Wiley S.R. Kraus R.J. Mertz J.E. Mol. Endocrinol. 1997; 11: 342-352Crossref PubMed Scopus (162) Google Scholar, 23Vanacker J.M. Bonnelye E. Delmarre C. Laudet V. Oncogene. 1998; 17: 2429-2435Crossref PubMed Scopus (64) Google Scholar, 24Vanacker J.M. Pettersson K. Gustafsson J.A. Laudet V. EMBO J. 1999; 18: 4270-4279Crossref PubMed Scopus (291) Google Scholar, 25Vanacker J.M. Bonnelye E. Chopin-Delannoy S. Delmarre C. Cavailles V. Laudet V. Mol. Endocrinol. 1999; 5: 764-773Google Scholar, 26Xie W. Hong H. Yang N.N. Lin R.J. Simon C.M. Stallcup M.R. Evans R.M. Mol. Endocrinol. 1999; 12: 2151-2162Crossref Scopus (127) Google Scholar, 27Zhang Z. Teng C.T. J. Biol. Chem. 2000; 275: 20837-20846Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar). ERRα has been implicated in various roles in bone and muscle development, modulation of aromatase expression in breast tissues, regulation of thyroid hormone receptor α (TRα) expression, overall development of mouse embryos, and fatty acid metabolism (21Bonnelye E. Vanacker J.M. Dittmar T. Begue A. Desbiens X. Denhardt D.T. Aubin J.E. Laudet V. Fournier B. Mol. Endocrinol. 1997; 7: 905-916Crossref Scopus (130) Google Scholar, 23Vanacker J.M. Bonnelye E. Delmarre C. Laudet V. Oncogene. 1998; 17: 2429-2435Crossref PubMed Scopus (64) Google Scholar, 28Bonnelye E. Vanacker J.M. Spruyt N. Alric S. Fournier B. Desbiens X. Laudet V. Mech. Dev. 1997; 65: 71-85Crossref PubMed Scopus (86) Google Scholar, 29Sladek R. Bader J.A. Giguere V. Mol. Cell. Biol. 1997; 9: 5400-5409Crossref Google Scholar, 30Yang C. Zhou D. Chen S. Cancer Res. 1998; 58: 5695-5700PubMed Google Scholar). Inactivation of the murine ERRβ gene caused severe placental abnormalities and embryonic mortality at 10.5 days post-coitum, and ERRβ has also been implicated in repression of glucocorticoid receptor-mediated transcriptional activities (31Luo J. Sladek R. Bader J-A. Rossant J. Giguere V. Nature. 1997; 388: 778-782Crossref PubMed Scopus (339) Google Scholar, 32Trapp T. Holsboer F. J. Biol. Chem. 1996; 271: 9879-9882Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar). The biological roles of ERRγ, the newest member of the subfamily, remain to be elucidated. The expression profiles of the three ERR isoforms show an overlapping pattern. ERRα mRNA is primarily expressed in tissues associated with fatty acid metabolism such as kidney, heart, and brown adipocytes. ERRγ is expressed at a high level in heart, brain, kidney, pancreas, and at a lower level in liver (5Hong H. Yang L. Stallcup M.R. J. Biol. Chem. 1999; 274: 22618-22626Abstract Full Text Full Text PDF PubMed Scopus (256) Google Scholar, 20Heard D.J. Norby P.L. Hollowa Y.J. Vissing H. Mol. Endocrinol. 2000; 14: 382-392Crossref PubMed Scopus (191) Google Scholar, 26Xie W. Hong H. Yang N.N. Lin R.J. Simon C.M. Stallcup M.R. Evans R.M. Mol. Endocrinol. 1999; 12: 2151-2162Crossref Scopus (127) Google Scholar), while the expression of its closer relative ERRβ is barely detectable in few tissues in adult rat including kidney, testis, heart, brain, and prostate. In the mouse ERRβ expression has been demonstrated in a subset of extraembryonic tissues in a small window between 5.5 days post-coitum and 8.5 days post-coitum (17Giguere V. Yang N. Segui P. Evans R.M. Nature. 1988; 331: 91-94Crossref PubMed Scopus (690) Google Scholar).Since the SHP gene promoter contains several SF-1 response elements that are predicted to be ERR response elements, we investigated whether ERR subfamily members can regulate theSHP gene promoter. Unexpectedly, transient transfection studies demonstrated a preferential effect of ERRγ on this promoter. Mapping studies revealed that only one of the five previously reported SF-1REs on SHP gene promoter is responsible for the ERRγ mediated activation of the SHP promoter. Electrophoretic mobility shift assays, and mutational studies confirmed the binding of ERRγ, to this element. As expected, SHP coexpression inhibits ERRγ transactivation of its own promoter, and SHP competes with the coactivator GRIP-1/SRC-2 for binding to ERRγ. We conclude that ERRγ is a component of a new potential autoregulatory loop controllingSHP gene expression.DISCUSSIONSeveral recent results have identified three nuclear receptors, SF-1, LRH-1, and FXR, as potential regulators of SHP expression. This is consistent with the relatively high levels of expression of SHP in tissues that express these three receptors including liver, adrenal, and pancreas. However, SHP is expressed in additional tissues, including heart, small intestine, stomach, epididymus, and prostate, several of which also express the orphan receptor ERRγ. Thus, it has been previously reported that murine ERRγ is expressed relatively highly in heart, brain, and kidney, with a lower expression in liver (5Hong H. Yang L. Stallcup M.R. J. Biol. Chem. 1999; 274: 22618-22626Abstract Full Text Full Text PDF PubMed Scopus (256) Google Scholar). Human ERRγ transcripts were found in heart, brain, placenta, kidney, pancreas, with a lower level of expression detected in spleen, thymus, prostate, testis, and small intestine (20Heard D.J. Norby P.L. Hollowa Y.J. Vissing H. Mol. Endocrinol. 2000; 14: 382-392Crossref PubMed Scopus (191) Google Scholar). In our study of human endocrine tissues, we found that both ERRγ and SHP are strongly expressed in pancreas, with a lower level of expression for both observed in adrenal medulla and cortex, stomach, and intestine. In mouse tissues, ERRγ expression was highest in the submaxillary gland, which also showed relatively high levels of SHP. Coexpression of ERRγ and SHP was also observed in heart, kidney, epididymus, prostate, and pancreas. Based on both this coexpression and its ability to transactivate the SHP promoter, we conclude that ERRγ is an additional potential regulator of SHP expression. As a consequence of the broad inhibitory functions of SHP, such regulation by ERRγ could have significant implications for nuclear receptor signaling pathways in a number of tissues.In addition to identifying a novel target gene for ERRγ, to our knowledge the first for this as yet poorly characterized receptor, these results also define unexpected DNA binding and functional properties for ERRγ. SF-1 requires at least three high affinity binding sites to efficiently transactivate the SHP promoter (16Lee Y.K. Parker K.L. Choi H.S. Moore D.D. J. Biol. Chem. 1999; 274: 20869-20873Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar). Although such SF-1 sites have been proposed to be targets for ERR family members, only the sft4 element showed such binding. Unexpectedly, although all three ERR family members bound this element with comparable affinity, only ERRγ significantly transactivated theSHP promoter in several different cell lines examined. Somewhat similar differential effects have been described in other contexts. Thus, a previous report demonstrated that ERRγ could efficiently bind a consensus SF-1RE/ERRE, TCAAGGTCA, but could only transactivate it weakly (20Heard D.J. Norby P.L. Hollowa Y.J. Vissing H. Mol. Endocrinol. 2000; 14: 382-392Crossref PubMed Scopus (191) Google Scholar). In agreement with this, we found that ERRγ exhibited insignificant activity on the TRαpromoter, which contains a perfect ERRE (23Vanacker J.M. Bonnelye E. Delmarre C. Laudet V. Oncogene. 1998; 17: 2429-2435Crossref PubMed Scopus (64) Google Scholar), whereas, on a five-copy SF-1RE reporter ERRγ demonstrated modest activity relative to that on a three-copy sft4 Luc (Fig. 4B). An additional study demonstrated ERRγ could not activate a palindromic thyroid hormone response element (TRE-Pal) (5Hong H. Yang L. Stallcup M.R. J. Biol. Chem. 1999; 274: 22618-22626Abstract Full Text Full Text PDF PubMed Scopus (256) Google Scholar), whereas both ERRα and ERRβ are known to bind this element and efficiently activate a reporter containing it (26Xie W. Hong H. Yang N.N. Lin R.J. Simon C.M. Stallcup M.R. Evans R.M. Mol. Endocrinol. 1999; 12: 2151-2162Crossref Scopus (127) Google Scholar). In our hands, ERRγ shows a modest activity on TRE inducing it by 1.5–2-fold in HeLa cells and DNA binding studies indicate that ERRγ binds TRE-Pal with a similar affinity as it binds sft4 (data not shown). The basis for the differential activities of the three ERR isoforms observed on SHP promoter is yet to be completely elucidated, but our results demonstrate differential effects of different DNA sequences on ERRγ tertiary structure. Protease sensitivity experiments performed on consensus SF-1RE, sft4, and TRE-Pal bound ERRγ or ERRα (Fig. 4, B and C, and data not shown) confirm this conclusion and suggest that DNA sequences may also act as allosteric modulator of ERRα structure. These effects are similar to those previously described for the GR and other nuclear receptors (36Starr D.B. Matsui W. Thomas J.R. Yamamoto K.R. Genes Dev. 1996; 10: 1271-1283Crossref PubMed Scopus (109) Google Scholar, 37Wood J.R. Likhite V.S. Loven M.A. Nardulli A.M. Mol. Endocrinol. 2001; 15: 1114-1126Crossref PubMed Scopus (105) Google Scholar, 38Wood J.R. Greene G.L. Nardulli A.M. Mol. Cell. Biol. 1998; 18: 1927-1934Crossref PubMed Scopus (107) Google Scholar, 39Ikeda M. Wilcox E.C. Chin W.W. J. Biol. Chem. 1996; 271: 23096-23104Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar).Although on sft4 TSA induced the activities of ERRα and -β but not ERRγ, we found that the activities of all three isoforms could be augmented by TSA treatment on ERE and TRE-Pal (Fig. 4A, and data not shown). The allosteric effects of DNA-binding sites on ERR structure suggest a specific mechanism for such differential transactivation. In this hypothesis, the structure of ERRα and -β bound to sft4 would be relatively permissive for corepressor binding, while the ERRγ-sft4 would be nonpermissive. It is also possible, of course, that allosteric effects of the DNA-binding site could alter interactions with coactivators, or with other DNA bound transcription factors. Detailed further studies will be required to test the potential importance of the differential effects of DNA sequence on ERR functions suggested by the initial results described here.The current study also demonstrates that SHP inhibits ERRγ transactivation. As with other receptors (5Hong H. Yang L. Stallcup M.R. J. Biol. Chem. 1999; 274: 22618-22626Abstract Full Text Full Text PDF PubMed Scopus (256) Google Scholar, 6Johansson L. Thomsen J.S. Damdimopoulos A.E. Spyrou G. Gustafsson J.A. Treuter E. J. Biol. Chem. 1999; 274: 345-353Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar) this inhibition is a consequence of a direct physical interaction of SHP with the AF-2 surface of ERRγ. Thus, in tissues where ERRγ is active, SHP should autoregulate its own gene expression. This mechanism should limit the response of not only SHP, but other ERRγ target genes to signals that increase ERRγ transactivation. The identification of such signals and such gene targets will be necessary to test this hypothesis.While this report was under review two reports demonstrated an antiestorgenic therapeutic drug, 4-hydroxytamoxifen, as a ligand for ERRβ and ERRγ (40Coward P. Lee D. Hull M.V. Lehmann J.M. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 8880-8884Crossref PubMed Scopus (234) Google Scholar, 41Tremblay G.B. Bergeron D. Giguere V. Endocrinology. 2001; 142: 4572-4575Crossref PubMed Scopus (101) Google Scholar). These reports, together with our report indicate that the SHP gene promoter may be a bona fide target of 4-hydroxytamoxifen. Further studies are needed to characterize such a possibility. The nuclear receptor superfamily is a diverse group of transcription factors that includes both conventional receptors with known ligands and orphan nuclear receptors that lack them (for reviews, see Refs. 1Evans R.M. Science. 1988; 240: 889-895Crossref PubMed Scopus (6292) Google Scholar and 2Giguere V. Endocr. Rev. 1999; 20: 689-725Crossref PubMed Scopus (707) Google Scholar). Both conventional and orphan nuclear receptors share a very similar structure. At the N terminus is a domain that is not conserved in sequence in different receptor families, but in many cases contains a ligand independent transcriptional activation domain termed activation function 1. The central DNA-binding domain (DBD)1 is strongly conserved and includes two zinc-binding units based on invariant cysteine residues. A conserved helical region within the DBD termed the P box (3Umesono K. Evans R.M. Cell. 1989; 57: 1139-1146Abstract Full Text PDF PubMed Scopus (720) Google Scholar) makes base specific contacts with hormone response elements. The sequence of this motif serves as one of the main criteria for dividing the nuclear receptor superfamily into subgroups. The C-terminal ligand-binding domain (LBD) functions not only in ligand binding, but also dimerization and ligand mediated transcriptional activation. This transactivation is based on an additional activation function referred to as AF-2. In most receptors, allosteric effects of ligand binding result in the formation of an appropriate binding site for a series of transcriptional coactivators. In a number of orphans, however, coactivator binding is not dependent on the presence of a ligand. Members of this subset of orphans, which includes HNF-4, and ERRγ, function as constitutive transactivators (4Hadzopoulou-Cladaras M. Kistanova E. Evagelopoulou C. Zeng S. Cladaras C. Ladias J.A. J. Biol. Chem. 1997; 272: 539-550Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar, 5Hong H. Yang L. Stallcup M.R. J. Biol. Chem. 1999; 274: 22618-22626Abstract Full Text Full Text PDF PubMed Scopus (256) Google Scholar). SHP is an atypical member of nuclear receptor superfamily that lacks a DBD. Various studies have reported SHP to be a repressor of transcriptional activities of a number of nuclear receptors, including both ligand responsive receptors like, ER, TR, RAR, and RXR, and orphan receptors like CAR, HNF-4, and FTF (6Johansson L. Thomsen J.S. Damdimopoulos A.E. Spyrou G. Gustafsson J.A. Treuter E. J. Biol. Chem. 1999; 274: 345-353Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar, 7Lee Y.K. Dell H. Dowhan D.H. Hadzopoulou-Cladaras M. Moore D.D. Mol. Cell. Biol. 2000; 20: 187-195Crossref PubMed Scopus (263) Google Scholar, 8Seol W. Choi H.S. Moore D.D. Science. 1996; 272: 1336-1339Crossref PubMed Scopus (438) Google Scholar, 9Seol W. Chung M. Moore D.D. Mol. Cell. Biol. 1997; 17: 7126-7131Crossref PubMed Scopus (118) Google Scholar, 10Seol W. Hanstein B. Brown M. Moore D.D. Mol. Endocrinol. 1998; 10: 1551-1557Crossref Scopus (126) Google Scholar). The very broad range of receptors sensitive to inhibition by SHP suggests a central role for SHP in modulation of nuclear receptor signaling pathways. Although the mechanisms underlying this repressive function remain unclear, recent results (7Lee Y.K. Dell H. Dowhan D.H. Hadzopoulou-Cladaras M. Moore D.D. Mol. Cell. Biol. 2000; 20: 187-195Crossref PubMed Scopus (263) Google Scholar, 11Johansson L. Bavner A. Thomsen J.S. Farnegardh M. Gustafsson J.A. Treuter E. Mol. Cell. Biol. 2000; 20: 1124-1133Crossref PubMed Scopus (132) Google Scholar) demonstrate that SHP can compete with coactivators for binding to the AF-2 surface. In addition, a direct transcriptional repressor domain contributes significantly to the inhibitory function of SHP. The SHP gene is structurally conserved in all the species from which it has been characterized. It consists of 2 exons interrupted by an intron and is located on human chromosome 1 at position 1p36.1 (12Lee H.K. Lee Y.K. Park S.H. Kim Y.S. Park S.H. Lee J.W. Kwon H.B. Soh J. Moore D.D. Choi H.S. J. Biol. Chem. 1998; 273: 14398-14440Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar). Initial studies indicated that SHP is expressed predominantly in the liver, spleen, small intestine, and pancreas (8Seol W. Choi H.S. Moore D.D. Science. 1996; 272: 1336-1339Crossref PubMed Scopus (438) Google Scholar,12Lee H.K. Lee Y.K. Park S.H. Kim Y.S. Park S.H. Lee J.W. Kwon H.B. Soh J. Moore D.D. Choi H.S. J. Biol. Chem. 1998; 273: 14398-14440Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar). However, later studies with more sensitive approaches have demonstrated the presence of SHP mRNA in a wide variety of tissues, with highest expression in heart, brain, liver, lung, and adrenal gland (11Johansson L. Bavner A. Thomsen" @default.
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• W2021082813 title "Differential Regulation of the Orphan Nuclear ReceptorSmall Heterodimer Partner (SHP) Gene Promoter by Orphan Nuclear Receptor ERR Isoforms" @default.
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