Key points are not available for this paper at this time.
The orphan nuclear hormone receptor liver receptor homologous protein-1 (LRH-1; NR5A2, also known as FTF), an unusual receptor that binds DNA as a monomer, is an essential regulator of expression of a rate-limiting enzyme in bile acid formation, cholesterol 7-α-hydroxylase. In a classic negative feedback loop that is a crucial component of the complex regulation of cholesterol metabolism, cholesterol 7-α-hydroxylase expression is decreased when bile acid levels are high. This repression is thought to be based on the bile acid-dependent induction of expression of the orphan receptor small heterodimer partner (SHP) NR0B2, which inhibits the activity of LRH-1. We have explored the molecular basis for this important regulatory effect by characterizing the mechanisms by which mouse and human SHP inhibit LRH-1-mediated transactivation. Both SHP proteins specifically interact with the AF-2 transactivation domain of LRH-1 both in vivo and in vitro. This domain is a common target for coactivator interaction, and the SHP proteins can compete with p160 coactivators for binding to LRH-1. In addition to the N-terminal receptor interaction domain, SHP includes a C-terminal domain with autonomous repression function. Neither a deletion nor a point mutation specifically affecting this domain blocked the ability to interact with LRH-1 to compete for coactivator binding or to repress LRH-1 transactivation. However, the relative ability of these mutants to inhibit LRH-1-mediated transactivation was markedly decreased. We conclude that the proposed central role of SHP in cholesterol metabolism is based on a two-step mechanism that is dependent on both coactivator competition and direct transcriptional repression. The orphan nuclear hormone receptor liver receptor homologous protein-1 (LRH-1; NR5A2, also known as FTF), an unusual receptor that binds DNA as a monomer, is an essential regulator of expression of a rate-limiting enzyme in bile acid formation, cholesterol 7-α-hydroxylase. In a classic negative feedback loop that is a crucial component of the complex regulation of cholesterol metabolism, cholesterol 7-α-hydroxylase expression is decreased when bile acid levels are high. This repression is thought to be based on the bile acid-dependent induction of expression of the orphan receptor small heterodimer partner (SHP) NR0B2, which inhibits the activity of LRH-1. We have explored the molecular basis for this important regulatory effect by characterizing the mechanisms by which mouse and human SHP inhibit LRH-1-mediated transactivation. Both SHP proteins specifically interact with the AF-2 transactivation domain of LRH-1 both in vivo and in vitro. This domain is a common target for coactivator interaction, and the SHP proteins can compete with p160 coactivators for binding to LRH-1. In addition to the N-terminal receptor interaction domain, SHP includes a C-terminal domain with autonomous repression function. Neither a deletion nor a point mutation specifically affecting this domain blocked the ability to interact with LRH-1 to compete for coactivator binding or to repress LRH-1 transactivation. However, the relative ability of these mutants to inhibit LRH-1-mediated transactivation was markedly decreased. We conclude that the proposed central role of SHP in cholesterol metabolism is based on a two-step mechanism that is dependent on both coactivator competition and direct transcriptional repression. small heterodimer partner liver receptor homologous protein-1 steroidogenic factor-1 retinoid X-receptor hepatocyte nuclear factor-4 glutathione S-transferase thymidine kinase dosage-sensitive sex reversal-adrenal hypoplasia congenita critical region on the X chromosome, gene 1 steroid receptor coactivator-3 The orphan receptor SHP1lacks the highly conserved DNA binding present in other members of the nuclear hormone receptor superfamily (1Seol W. Choi H.S. Moore D.D. Science. 1996; 272: 1336-1339Crossref PubMed Scopus (442) Google Scholar). Although SHP does not bind DNA directly, a number of reports demonstrate that SHP can interact with a variety of nuclear hormone receptors including the thyroid hormone receptor, the retinoic acid receptor, the peroxisome proliferator-activated receptor-α, the estrogen receptor-α, the retinoid-X-receptor (RXR), and the orphan receptor HNF-4 (1Seol W. Choi H.S. Moore D.D. Science. 1996; 272: 1336-1339Crossref PubMed Scopus (442) Google Scholar, 2Masuda N. Yasumo H. Tamura T. Hashiguchi N. Furusawa T. Tsukamoto T. Sadano H. Osumi T. Biochim. Biophys. Acta. 1997; 1350: 27-32Crossref PubMed Scopus (48) Google Scholar, 3Seol W. Chung M. Moore D.D. Mol. Cell. Biol. 1997; 17: 7126-7131Crossref PubMed Scopus (118) Google Scholar, 4Seol W. Hanstein B. Brown M. Moore D.D. Mol. Endocrinol. 1998; 12: 1551-1557Crossref PubMed Scopus (0) Google Scholar, 5Johansson L. Thomsen J.S. Damdimopoulos A.E. Spyrou G. Gustafsson J. Treuter E. J. Biol. Chem. 1999; 274: 345-353Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar, 6Lee Y.K. Dell H. Dowhan D.H. Hadzopoulou-Cladaras M. Moore D.D. Mol. Cell. Biol. 2000; 20: 187-195Crossref PubMed Scopus (265) Google Scholar). These interactions result in repression of the transcriptional activities of such SHP targets. Initial results with retinoic acid receptor-RXR heterodimers indicated that SHP can inhibit DNA binding in some cases (1Seol W. Choi H.S. Moore D.D. Science. 1996; 272: 1336-1339Crossref PubMed Scopus (442) Google Scholar). However, the identification of an autonomous repression function of SHP suggested the existence of additional repression mechanisms for SHP (3Seol W. Chung M. Moore D.D. Mol. Cell. Biol. 1997; 17: 7126-7131Crossref PubMed Scopus (118) Google Scholar). This function could be particularly important for target receptors that bind DNA as monomers, because such receptors would not be sensitive to inhibitory processes based on disrupting dimeric complexes. More recent results have demonstrated that SHP can also inhibit transactivation by several receptors that bind DNA as homodimers, including estrogen receptor, RXR, and HNF-4 (4Seol W. Hanstein B. Brown M. Moore D.D. Mol. Endocrinol. 1998; 12: 1551-1557Crossref PubMed Scopus (0) Google Scholar, 5Johansson L. Thomsen J.S. Damdimopoulos A.E. Spyrou G. Gustafsson J. Treuter E. J. Biol. Chem. 1999; 274: 345-353Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar, 6Lee Y.K. Dell H. Dowhan D.H. Hadzopoulou-Cladaras M. Moore D.D. Mol. Cell. Biol. 2000; 20: 187-195Crossref PubMed Scopus (265) Google Scholar). This repression does not appear to involve effects on DNA binding and is thought to be dependent on a two-step mechanism in which SHP decreases transactivation, first by competing with p160 coactivators for binding to the nuclear receptors and second by the actions of the as yet poorly characterized autonomous SHP repression activity (3Seol W. Chung M. Moore D.D. Mol. Cell. Biol. 1997; 17: 7126-7131Crossref PubMed Scopus (118) Google Scholar, 6Lee Y.K. Dell H. Dowhan D.H. Hadzopoulou-Cladaras M. Moore D.D. Mol. Cell. Biol. 2000; 20: 187-195Crossref PubMed Scopus (265) Google Scholar). Recent results have suggested that the orphan receptor LRH-1 is a particularly crucial target for the inhibitory effects of SHP (7Goodwin 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. 2000; 6: 517-526Abstract Full Text Full Text PDF PubMed Scopus (1513) Google Scholar, 8Lu 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 (1228) Google Scholar). LRH-1 is a liver-enriched transcription factor that is closely related to the orphan SF-1, which is essential for sexual differentiation and development of tissues in which it is expressed including adrenals and gonads (9Shen W.H. Moore C.C. Ikeda Y. Parker K.L. Ingraham H.A. Cell. 1994; 77: 651-661Abstract Full Text PDF PubMed Scopus (491) Google Scholar, 10Luo X. Ikeda Y. Parker K.L. Cell. 1994; 77: 481-490Abstract Full Text PDF PubMed Scopus (1384) Google Scholar). The DNA-binding domain of LRH-1 shares over a 90% identity and 95% similarity with that of SF-1, and both bind with high affinity as monomers to a conserved core DNA motif present in the promoters of target genes (7Goodwin 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. 2000; 6: 517-526Abstract Full Text Full Text PDF PubMed Scopus (1513) Google Scholar, 8Lu 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 (1228) Google Scholar, 9Shen W.H. Moore C.C. Ikeda Y. Parker K.L. Ingraham H.A. Cell. 1994; 77: 651-661Abstract Full Text PDF PubMed Scopus (491) Google Scholar, 11Galarneau L. Pare J.F. Allard D. Hamel D. Levesque L. Tugwood J.D. Green S. Belanger L. Mol. Cell. Biol. 1996; 16: 3853-3865Crossref PubMed Google Scholar, 12Li M. Xie Y.H. Kong Y.Y. Wu X. Zhu L. Wang Y. J. Biol. Chem. 1998; 273: 29022-29031Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar, 13Nitta M. Ku S. Brown C. Okamoto A.Y. Shan B. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 6660-6665Crossref PubMed Scopus (249) Google Scholar, 14Gilbert S. Galarneau L. Lamontagne A. Roy S. Belanger L. J. Virol. 2000; 74: 5032-5039Crossref PubMed Scopus (44) Google Scholar). Earlier, we reported that either SF-1 or LRH-1 could transactivate the SHP promoter, which contains several such motifs (15Lee 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). The existence of a negative feedback regulation of SHP expression, at least in liver, was suggested by the observation that LRH-1 transactivation was particularly sensitive to inhibition by SHP. However, this effect may be limited to liver, because SF-1 was relatively resistant to the effects of SHP. More recent data also suggest that LRH-1 is essential for expression of the cytochrome p450 7A(CYP7A1) gene, which encodes cholesterol 7α-hydroxylase, a rate-limiting enzyme in the conversion of hepatic cholesterol to bile acids (7Goodwin 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. 2000; 6: 517-526Abstract Full Text Full Text PDF PubMed Scopus (1513) Google Scholar, 8Lu 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 (1228) Google Scholar, 13Nitta M. Ku S. Brown C. Okamoto A.Y. Shan B. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 6660-6665Crossref PubMed Scopus (249) Google Scholar). Increased levels of bile acids are thought to result in decreased CYP7A gene expression through a novel indirect feedback loop in which increased levels of bile acids stimulate SHP gene expression via activation of the bile acid receptor FXR (Farnesoid X receptor) (7Goodwin 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. 2000; 6: 517-526Abstract Full Text Full Text PDF PubMed Scopus (1513) Google Scholar, 8Lu 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 (1228) Google Scholar). In this mechanism, the functional interaction of SHP and LRH-1 is the linchpin of a central axis in cholesterol regulation. The molecular basis for SHP inhibition of LRH-1 transactivation has not been defined. Although the mechanisms for the effects of SHP on other targets have been explored, unique aspects of the functional interaction of SHP with LRH-1 and SF-1 raise the possibility of distinct mechanisms for these proteins. Thus, the function of these two receptors as monomers suggests that their interactions with both DNA and coactivators may differ significantly from those of other receptors. This possibility is strongly supported by some unusual transactivation functions of SF-1 (16Nachtigal M.W. Hirokawa Y. Enyeart-VanHouten D.L. Flanagan J.N. Hammer G.D. Ingraham H.A. Cell. 1998; 93: 445-454Abstract Full Text Full Text PDF PubMed Scopus (494) Google Scholar, 17Hammer G.D. Krylova I. Zhang Y. Darimont B.D. Simpson K. Weigel N.L. Ingraham H.A. Mol. Cell. 1999; 3: 521-526Abstract Full Text Full Text PDF PubMed Scopus (327) Google Scholar), which may underlie the lack of inhibition of SF-1 by SHP. It remains uncertain whether LRH-1 transactivation is associated with such unusual mechanisms. Prompted by both the importance of the functional interaction between SHP and LRH-1 and this uncertainty, we have characterized the mechanisms by which SHP inhibits LRH-1 transactivation. SHP did not inhibit LRH-1 DNA binding. As observed with the homodimeric receptors HNF-4, RXR, and estrogen receptor, SHP did compete with p160 coactivators for binding to LRH-1. SHP mutants, retaining the receptor interaction function but lacking the autonomous repression function due to either a deletion (mSHPW160X) (3Seol W. Chung M. Moore D.D. Mol. Cell. Biol. 1997; 17: 7126-7131Crossref PubMed Scopus (118) Google Scholar) or a point mutation (hSHPR213C) (18Nishigori H. Tomura H. Tonooka N. Kanamori M. Yamada S. Sho K. Inoue I. Kikuchi N. Onigata K. Kojima I. Kohama T. Yamagata K. Yang Q. Matsuzawa Y. Miki T. Seino S. Kim M.Y. Choi H.S. Lee Y.K. Moore D.D. Takeda J. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 575-580Crossref PubMed Scopus (137) Google Scholar), were able to inhibit LRH-1 transactivation. However, the limited extent of this repression suggests that active repression by SHP is essential for efficient LRH-1 inhibition as described for RXR and estrogen receptor. We conclude that the previously described two-step process involving both coactivator competition and direct repression is conserved in the SHP inhibition of transactivation by the monomeric orphan receptor LRH-1. HepG2 cells were maintained in 75-cm2 tissue culture flasks with Dulbecco's modified Eagle's medium plus 10% fetal bovine serum. One day before transfection, confluent cells were trypsinized and with a to the cells to at the of were with medium 1 before were the with of both the and and the indicated of expression as described previously Y.K. Dell H. Dowhan D.H. Hadzopoulou-Cladaras M. Moore D.D. Mol. Cell. Biol. 2000; 20: 187-195Crossref PubMed Scopus (265) Google Scholar). expression was and hormone expression were the of were described previously Y.K. Dell H. Dowhan D.H. Hadzopoulou-Cladaras M. Moore D.D. Mol. Cell. Biol. 2000; 20: 187-195Crossref PubMed Scopus (265) Google Scholar, 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) with the of the and human SHP was by with to the C-terminal AF-2 core motif of Both the and of LRH-1 and the domain of LRH-1 acids human SHP was from number was to and The was were by DNA The was to interaction in vitro. or proteins were expressed in and were to with target proteins were for and proteins were by with a and proteins were by with to and by The of specifically proteins was a the repression of LRH-1 transcriptional activity by we a with a previously described in which gene expression Y. X. Kim E. Parker K.L. Mol. Endocrinol. PubMed Google Scholar). As from their conserved DNA-binding L. Pare J.F. Allard D. Hamel D. Levesque L. Tugwood J.D. Green S. Belanger L. Mol. Cell. Biol. 1996; 16: 3853-3865Crossref PubMed Google Scholar), this SF-1 was strongly by LRH-1 and the of mouse SHP LRH-1-mediated transactivation in a results were observed with the SHP not This inhibition is not dependent on decreased DNA binding by because the addition of SHP did not the of an by LRH-1 in as by the not SHP transactivation by the in which the DNA-binding domain that of LRH-1 This repression was particularly of SHP expression transactivation by of the and of the SHP decreased expression to of the observed with the or 1 and with This repression is with results with RXR Y.K. Dell H. Dowhan D.H. Hadzopoulou-Cladaras M. Moore D.D. Mol. Cell. Biol. 2000; 20: 187-195Crossref PubMed Scopus (265) Google Scholar) and suggests an important function for the autonomous repression function of SHP in LRH-1 this a previously characterized SHP lacking the C-terminal autonomous repression domain of C-terminal acids was This also transactivation by either the LRH-1 or but with significantly to transactivation at not We also human SHP for repression on this As in human SHP also the LRH-1-mediated transactivation However, this was significantly decreased by a human SHP mutation previously associated with in (18Nishigori H. Tomura H. Tonooka N. Kanamori M. Yamada S. Sho K. Inoue I. Kikuchi N. Onigata K. Kojima I. Kohama T. Yamagata K. Yang Q. Matsuzawa Y. Miki T. Seino S. Kim M.Y. Choi H.S. Lee Y.K. Moore D.D. Takeda J. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 575-580Crossref PubMed Scopus (137) Google Scholar). This is with the decreased inhibitory effect of this mutation on HNF-4 transactivation, and with the results described this suggests that this mutation specifically the SHP autonomous repression we have that SHP specifically the AF-2 of nuclear receptors for both interaction and repression Y.K. Dell H. Dowhan D.H. Hadzopoulou-Cladaras M. Moore D.D. Mol. Cell. Biol. 2000; 20: 187-195Crossref PubMed Scopus (265) Google Scholar). whether SHP also targets AF-2 of the monomeric a deletion of the conserved acid motif of the of LRH-1 was in the of a activation domain The ability of or the to interact with and was the As in a interaction with both of the which was by the AF-2 mutation in In with these SHP in with a expressed but not with The ability of the to interact with was also This binding as from this was decreased of of SHP and The human was also for interaction with LRH-1 the The interaction of with LRH-1 was from that of SHP of and SHP interaction between mouse SHP or and LRH-1 in and and were expressed in E. to and for interaction with SHP or by in transcription and proteins were and by The of of was by the of the were a The was by to the interaction of human SHP or the SHP with LRH-1 in HepG2 cells were with of or of or of and of as an We have previously described a modified to the ability of a to the interaction between two and Y.K. Dell H. Dowhan D.H. Hadzopoulou-Cladaras M. Moore D.D. Mol. Cell. Biol. 2000; 20: 187-195Crossref PubMed Scopus (265) Google Scholar). We this to whether SHP and coactivators compete for interaction with LRH-1. relatively transactivation was observed when a the receptor interaction domain of the p160 coactivator known as was with in HepG2 a interaction of LRH-1 with such interaction was observed with the and that the AF-2 is for this interaction not As described previously Y.K. Dell H. Dowhan D.H. Hadzopoulou-Cladaras M. Moore D.D. Mol. Cell. Biol. 2000; 20: 187-195Crossref PubMed Scopus (265) Google Scholar), a transcriptional activation domain was the for competition to the SHP expression function. Thus, the inhibitory effects observed are not a of of the SHP repression function a of or and strongly decreased the interaction, that SHP can compete for LRH-1 binding with The result has been with of SHP. levels of also decreased this interaction, but in with the were efficient the SHP. In with for binding to LRH-1 as as and with that this mutation does not receptor binding. The orphan nuclear receptor SHP a DNA-binding domain and inhibitory effects through interactions (1Seol W. Choi H.S. Moore D.D. Science. 1996; 272: 1336-1339Crossref PubMed Scopus (442) Google Scholar, 2Masuda N. Yasumo H. Tamura T. Hashiguchi N. Furusawa T. Tsukamoto T. Sadano H. Osumi T. Biochim. Biophys. Acta. 1997; 1350: 27-32Crossref PubMed Scopus (48) Google Scholar, 3Seol W. Chung M. Moore D.D. Mol. Cell. Biol. 1997; 17: 7126-7131Crossref PubMed Scopus (118) Google Scholar, 4Seol W. Hanstein B. Brown M. Moore D.D. Mol. Endocrinol. 1998; 12: 1551-1557Crossref PubMed Scopus (0) Google Scholar, 5Johansson L. Thomsen J.S. Damdimopoulos A.E. Spyrou G. Gustafsson J. Treuter E. J. Biol. Chem. 1999; 274: 345-353Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar, 6Lee Y.K. Dell H. Dowhan D.H. Hadzopoulou-Cladaras M. Moore D.D. Mol. Cell. Biol. 2000; 20: 187-195Crossref PubMed Scopus (265) Google Scholar). The results described demonstrate that SHP with the orphan receptor which binds DNA as a These data are with results with other receptors and the of the functional interaction of the two orphan receptors (7Goodwin 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. 2000; 6: 517-526Abstract Full Text Full Text PDF PubMed Scopus (1513) Google Scholar, 8Lu 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 (1228) Google Scholar, 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). However, several suggested the possibility that the interactions of these two unusual differ from those described previously for SHP. As a monomer, the interactions of LRH-1 with both DNA and coactivators differ from those of the of receptors that function as Thus, the effects of SHP on these interactions be to differ from those on the dimeric receptors. This is particularly for SF-1, which has been to have unusual interactions (16Nachtigal M.W. Hirokawa Y. Enyeart-VanHouten D.L. Flanagan J.N. Hammer G.D. Ingraham H.A. Cell. 1998; 93: 445-454Abstract Full Text Full Text PDF PubMed Scopus (494) Google Scholar) and transactivation functions G.D. Krylova I. Zhang Y. Darimont B.D. Simpson K. Weigel N.L. Ingraham H.A. Mol. Cell. 1999; 3: 521-526Abstract Full Text Full Text PDF PubMed Scopus (327) Google Scholar) that may be to the of inhibitory effects of SHP. In the of LRH-1 transactivation, the mechanisms of inhibition by SHP The that this inhibition has been proposed to a crucial role in cholesterol metabolism the importance of molecular The results described demonstrate that SHP targets the AF-2 of LRH-1 and with coactivators for binding to the to the target receptor and to the autonomous repression function of SHP to the inhibitory Both of these effects are to those described for other and we conclude that the two-step mechanism for repression is a of SHP inhibition of transactivation by both dimeric and monomeric nuclear receptors. The molecular basis for the function of the SHP repression domain remains we have not been able to demonstrate interaction between SHP and previously including or In a of has effect on the SHP repression. Although these results suggest that SHP effects on target gene promoters by a mechanism distinct from those previously described for nuclear hormone receptors. It is that in this the which results from SHP binding to an receptor, could be from that by the of for thyroid hormone receptor or retinoic acid receptor, for a of SHP gene function was associated with a of in a number of (18Nishigori H. Tomura H. Tonooka N. Kanamori M. Yamada S. Sho K. Inoue I. Kikuchi N. Onigata K. Kojima I. Kohama T. Yamagata K. Yang Q. Matsuzawa Y. Miki T. Seino S. Kim M.Y. Choi H.S. Lee Y.K. Moore D.D. Takeda J. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 575-580Crossref PubMed Scopus (137) Google Scholar). This suggests a function for SHP in regulation the effects on cholesterol metabolism from effects on LRH-1 (7Goodwin 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. 2000; 6: 517-526Abstract Full Text Full Text PDF PubMed Scopus (1513) Google Scholar, 8Lu 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 (1228) Google Scholar, 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). functional be to the functions of the of these human gene may some SHP repression. of the are but of are point that a relatively of the repression domain acids the of these SHP point mutants are in the repression of HNF-4 transactivation. As indicated by the results described of the (hSHPR213C) has a effect on the autonomous repression function. of the functional effects of these may to the mechanism of repression by SHP. The interaction between SHP and LRH-1 shares both and with the previously described interaction between and SF-1 M. Mol. Cell. Biol. 1997; 17: PubMed Scopus Google Scholar). on both similarity and direct identity in the is the relative to SHP. SF-1 and LRH-1 are with a identity in the domain and 90% identity in the DNA-binding domain, for their highly DNA-binding Both SHP and inhibit transactivation of their nuclear receptor and both interact with receptor via motifs to those present in p160 and other coactivators H. Thomsen J.S. L. Gustafsson Treuter E. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, L. A. Thomsen J.S. M. Gustafsson Treuter E. Mol. Cell. Biol. 2000; 20: PubMed Scopus Google Scholar). In both SHP and autonomous repression functions that are in the C-terminal and that specifically this region have been in human (3Seol W. Chung M. Moore D.D. Mol. Cell. Biol. 1997; 17: 7126-7131Crossref PubMed Scopus (118) Google Scholar, H. Tomura H. Tonooka N. Kanamori M. Yamada S. Sho K. Inoue I. Kikuchi N. Onigata K. Kojima I. Kohama T. Yamagata K. Yang Q. Matsuzawa Y. Miki T. Seino S. Kim M.Y. Choi H.S. Lee Y.K. Moore D.D. Takeda J. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 575-580Crossref PubMed Scopus (137) Google Scholar, E. B. E. T.M. D. Mol. Endocrinol. 1997; PubMed Scopus Google Scholar, M. Mol. Cell. Biol. 1997; 17: PubMed Scopus Google Scholar). However, the inhibitory targets of appear those of SHP. In has been reported to such as and and does not the AF-2 of SF-1 for interaction and repression C. Y. J. Mol. Cell. Biol. 1998; PubMed Scopus Google Scholar, B. U. D. A. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). on these may either the or their functional
Lee et al. (Tue,) studied this question.