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• W2067207360 abstract "The Oct-3/4 transcription factor is expressed in the earliest stages of embryogenesis, and is thus likely to play an important role in regulation of initial decisions in development. For the first time, we have shown that SF1 and Oct-3/4 are co-expressed in embryonal carcinoma (EC) P19 cells, and their expression is down-regulated with very similar kinetics following retinoic acid (RA) induced differentiation of these cells, suggesting a functional relationship between the two. Previously, we have shown that theOct-3/4 promoter harbors an RA-responsive element, RAREoct, which functions in EC cells as a binding site for positive regulators of transcription, such as RAR and RXR. In this study we have identified in the Oct-3/4 promoter two novel SF1-binding sites: SF1(a) and SF1(b). The proximal site, SF1(a), is located within the RAREoct, and the distal site, SF1(b), is located between nucleotide −193 and −209 of the Oct-3/4 promoter. Both sites contribute to activation of Oct-3/4 promoter in EC cells, with SF1(a) playing a more crucial role. SF1, and its isoforms ELP2 and ELP3 bind to both SF1 sites and activate the Oct-3/4 promoter. This activation depends on the presence of SF1 DNA-binding domain. Thus,Oct-3/4 is the first EC-specific gene reported that is regulated by SF1. Interestingly, SF1 and RAR form a novel complex on the RAREoct sequence that synergistically activate theOct-3/4 promoter. Both RARE and SF1 cisregulatory elements, as well as the SF1 DNA-binding domain, are needed for this synergism. SF1 and Oct-3/4 transcription factors play a role in the same developmental regulatory cascade. The Oct-3/4 transcription factor is expressed in the earliest stages of embryogenesis, and is thus likely to play an important role in regulation of initial decisions in development. For the first time, we have shown that SF1 and Oct-3/4 are co-expressed in embryonal carcinoma (EC) P19 cells, and their expression is down-regulated with very similar kinetics following retinoic acid (RA) induced differentiation of these cells, suggesting a functional relationship between the two. Previously, we have shown that theOct-3/4 promoter harbors an RA-responsive element, RAREoct, which functions in EC cells as a binding site for positive regulators of transcription, such as RAR and RXR. In this study we have identified in the Oct-3/4 promoter two novel SF1-binding sites: SF1(a) and SF1(b). The proximal site, SF1(a), is located within the RAREoct, and the distal site, SF1(b), is located between nucleotide −193 and −209 of the Oct-3/4 promoter. Both sites contribute to activation of Oct-3/4 promoter in EC cells, with SF1(a) playing a more crucial role. SF1, and its isoforms ELP2 and ELP3 bind to both SF1 sites and activate the Oct-3/4 promoter. This activation depends on the presence of SF1 DNA-binding domain. Thus,Oct-3/4 is the first EC-specific gene reported that is regulated by SF1. Interestingly, SF1 and RAR form a novel complex on the RAREoct sequence that synergistically activate theOct-3/4 promoter. Both RARE and SF1 cisregulatory elements, as well as the SF1 DNA-binding domain, are needed for this synergism. SF1 and Oct-3/4 transcription factors play a role in the same developmental regulatory cascade. embryonic stem cells octamer-binding protein 3/4 steroiodogenic factor-1 embryonal long terminal repeat protein embryonal carcinoma retinoic acid RA receptors retinoid X receptors RA responsive element of the Oct-3/4promoter DNA-binding domain upstream promoter element whole cell extract kilobase pair(s) base pair(s) chloramphenicol acetyltransferase Transcription factors play a critical role in embryonic development and cellular differentiation. One family of transcription factors which exhibits developmental functions is the POU-specific family. Members of this family share two regions of homology: a highly conserved amino-terminal domain, designated the POU-specific domain, and a more divergent carboxyl-terminal homeodomain (reviewed in Refs. 1.Ryan A.K. Rosenfeld M.G. Genes Dev. 1997; 11: 1207-1225Crossref PubMed Scopus (439) Google Scholarand 2.Verrijzer C.P. Van der Vliet P.C. Biochim. Biophys. Acta. 1993; 1173: 1-21Crossref PubMed Scopus (243) Google Scholar).The Oct-3/4 gene product is a member of the POU-specific family of transcription factors (3.Schöler H.R. Trends Genet. 1991; 7: 323-329Abstract Full Text PDF PubMed Scopus (328) Google Scholar). It is expressed in totipotent and pluripotent stem cells of the pregastrulation embryo, primordial germ cells, and oocytes (4.Okamoto K. Okazawa H. Okuda A. Sakai M. Muramatsu M. Hamada H. Cell. 1990; 60: 461-472Abstract Full Text PDF PubMed Scopus (607) Google Scholar, 5.Rosner M.H. Vigano M.A. Ozato K. Timmons P.M. Poirier F. Rigby P.W.J. Staudt L.M. Nature. 1990; 345: 686-692Crossref PubMed Scopus (755) Google Scholar, 6.Schöler H.R. Ruppert S. Suzuki N. Chowdhury K. Gruss P. Nature. 1990; 344: 435-439Crossref PubMed Scopus (591) Google Scholar, 7.Schöler H.R. Dressler G.R. Balling R. Rohdewohld H. Gruss P. EMBO J. 1990; 9: 2185-2195Crossref PubMed Scopus (492) Google Scholar). Oct-3/4 is also highly expressed in embryonic stem (ES)1 and embryonal carcinoma (EC) cell lines. Oct-3/4 expression is down-regulated in the developing embryo upon differentiation to endoderm and mesoderm, and in EC and ES cells which are induced to differentiate in vitro following treatment with retinoic acid (EC/RA, ES/RA) (4.Okamoto K. Okazawa H. Okuda A. Sakai M. Muramatsu M. Hamada H. Cell. 1990; 60: 461-472Abstract Full Text PDF PubMed Scopus (607) Google Scholar, 5.Rosner M.H. Vigano M.A. Ozato K. Timmons P.M. Poirier F. Rigby P.W.J. Staudt L.M. Nature. 1990; 345: 686-692Crossref PubMed Scopus (755) Google Scholar, 7.Schöler H.R. Dressler G.R. Balling R. Rohdewohld H. Gruss P. EMBO J. 1990; 9: 2185-2195Crossref PubMed Scopus (492) Google Scholar, 8.Palmieri S.L. Peter W. Hess H. Schöler H.R. Dev. Biol. 1994; 166: 259-267Crossref PubMed Scopus (523) Google Scholar, 9.Schöler H.R. Balling R. Hatzopoulos K. Suzuki N. Gruss P. EMBO J. 1989; 8: 2551-2557Crossref PubMed Scopus (263) Google Scholar). Expression of Oct-3/4 is crucial to the establishment of pluripotent stem cells in the mammalian embryo, since Oct-3/4-deficient embryos develop to the blastocyst stage, but the inner cell mass cells are not pluripotent (10.Nichols J. Zevnik B. Anastassiadis K. Niwa H. Klewe-Nebenius D. Chambers I. Schöler H. Smith A. Cell. 1998; 95: 379-391Abstract Full Text Full Text PDF PubMed Scopus (2639) Google Scholar).Studies of the down-regulation of Oct-3/4 gene expression suggest an involvement of several cis acting elements. An enhancer element (located 1.2 kb upstream of the initiation site, designated RARE1) has been characterized (11.Okazawa H. Okamoto K. Ishino F. Ishino-Kaneko T. Takeda S. Toyoda Y. Muramatsu M. Hamada H. EMBO J. 1991; 10: 2997-3005Crossref PubMed Scopus (156) Google Scholar). This enhancer is necessary for a high level of promoter activity in P19 cells before RA treatment and for RA-mediated repression. Another DNA element located farther upstream (∼2 kb 5′ to the initiation site) and designated the distal enhancer has also been identified (12.Minucci S. Botquin V. Yeom Y.-I. Dey A. Sylvester I. Zand D.J. Ohbo K. Ozato K. Schöler H.R. EMBO J. 1996; 15: 888-899Crossref PubMed Scopus (85) Google Scholar, 13.Young Y., II Fuhrmann G. Ovitt C.E. Brehm A. Ohbo K. Gross M. Hübner K. Schöler H.R. Development. 1996; 122: 881-894Crossref PubMed Google Scholar). This element confers strong enhancer activity in ES cells, but not EC cells, and in mice is considered to be active specifically in the germ line lineage. We and others have previously detected an RA-responsive element, RAREoct, present in the promoter region of the Oct-3/4 gene (14.Pikarsky E. Sharir H. Ben-Shushan E. Bergman Y. Mol. Cell. Biol. 1994; 14: 1026-1038Crossref PubMed Scopus (105) Google Scholar, 15.Schoorlemmer J. van Puijenbroek A. van den Eijnden M. Jonk L. Pals C. Kruijer W. Mol. Cell. Biol. 1994; 14: 1122-1136Crossref PubMed Scopus (91) Google Scholar, 16.Sylvester I. Schöler H.R. Nucleic Acids Res. 1994; 22: 901-911Crossref PubMed Scopus (73) Google Scholar). This RAREoct motif functions in EC cells as a binding site for positive regulators of transcription, and in RA-differentiated cells as a binding site for negative regulators (15.Schoorlemmer J. van Puijenbroek A. van den Eijnden M. Jonk L. Pals C. Kruijer W. Mol. Cell. Biol. 1994; 14: 1122-1136Crossref PubMed Scopus (91) Google Scholar, 16.Sylvester I. Schöler H.R. Nucleic Acids Res. 1994; 22: 901-911Crossref PubMed Scopus (73) Google Scholar, 17.Ben-Shushan E. Sharir H. Pikarsky E. Bergman Y. Mol. Cell. Biol. 1995; 15: 1034-1048Crossref PubMed Google Scholar). Unlike the RARE1 region located in the proximal enhancer, the RAREoct promoter element contains a typical recognition sequence for RA receptors (RAR).Vitamin A (retinol) and its biologically active derivatives (retinoids), most notably RA, exert pleiotropic effects on vertebrate development, cell differentiation, and homeostasis (18.Mendelsohn C. Ruberte E. Chambon P. Dev. Biol. 1992; 152: 50-61Crossref PubMed Scopus (93) Google Scholar, 19.Tabin C.J. Cell. 1991; 66: 199-217Abstract Full Text PDF PubMed Scopus (365) Google Scholar). The action of diverse ligands (including retinoids, vitamin D, steroid hormones, and thyroid hormone) is mediated by members of the nuclear hormone receptor superfamily. RA exerts its action through two distinct groups within the nuclear hormone receptor superfamily: the retinoid nuclear receptors, RARs (isoforms α, β, and γ), and the RXRs (isoforms α, β, and γ). The complexity of retinoid signaling is further increased by the fact that, at least in vitro, RARs bind to their polymorphic cis acting response elements, as RAR:RXR heterodimers. Moreover, RXRs are also heterodimeric partners for other nuclear receptors such as thyroid hormone, vitamin D3, and peroxisome proliferator-activated receptors, as well as the nerve growth factor I-B (NGFI-B) (reviewed in Refs. 20.Chambon P. FASEB J. 1996; 10: 940-954Crossref PubMed Scopus (2587) Google Scholar and 21.Kastner P. Mark M. Chambon P. Cell. 1995; 83: 859-869Abstract Full Text PDF PubMed Scopus (933) Google Scholar), and the OR1 orphan receptors (22.Wiebel F.F. Gustafsson J.-A. Mol. Cell. Biol. 1997; 17: 3977-3986Crossref PubMed Google Scholar). The orphan members of the nuclear receptor family of transcription factors are those for which the activating ligands have not been identified. Two of the well characterized orphan receptors, ARP-I and COUP-TFI, were shown to have the capacity to block RAR:RXR-mediated transactivation (23.Cooney A.J. Tsai S.Y. O'Malley B.W. Tsai M.-J. Mol. Cell. Biol. 1992; 12: 4153-4163Crossref PubMed Scopus (335) Google Scholar, 24.Tran P. Zhang X.-K. Salbert G. Hermann T. Lehmann J.M. Pfahl M. Mol. Cell. Biol. 1992; 12: 4666-4676Crossref PubMed Scopus (199) Google Scholar). Previous work in our laboratory indicated inhibition of Oct-3/4 gene expression by the ARP-I and COUP-TFI orphan receptors through the RAREoct site (17.Ben-Shushan E. Sharir H. Pikarsky E. Bergman Y. Mol. Cell. Biol. 1995; 15: 1034-1048Crossref PubMed Google Scholar).The RAREoct sequence includes a potential site for the binding of another orphan receptor, steroidogenic factor-1 (SF1). SF1 has emerged as a key regulator of endocrine function within the hypothalamic-pituitary-gonadal axis and adrenal cortex and as an essential factor in sex differentiation. SF1 plays a role in the regulation of genes in steroidogenic cells, Sertoli cells, and gonadotropes. Analysis of the role of SF1 in vivo by targeted gene disruption showed that SF1 knockout mice exhibited adrenal and gonadal agenesis, male-to-female sex reversal of the internal and external genitalia, impaired gonadotrope function, and deletion of a specific region of the hypothalamus (reviewed in Ref.25.Parker K.L. Schimmer B.P. Endocr. Rev. 1997; 18: 361-377Crossref PubMed Scopus (556) Google Scholar). The SF1 protein is one of four known isoforms (SF-1, ELP1, ELP2, and ELP3) generated by alternative promoter usage and 3′-splicing of the same gene (26.Ninomiya Y. Okada M. Kotomura N. Suzuki K. Tsukiyama T. Niwa O. J. Biochem. (Tokyo). 1995; 118: 380-389Crossref PubMed Scopus (53) Google Scholar). The SF-1/ELP transcription factors and their closely resembled Drosophila fushi tarazu factor 1 are believed to interact with their recognition site 5′-PyCAAGGPyCPu-3′ or 5′-PuPuAGGTC-3′ as monomers (27.Ohno C.K. Ueda H. Petkovich M. Mol. Cell. Biol. 1994; 14: 3166-3175Crossref PubMed Google Scholar, 28.Ueda H. Sun G.-C. Murata T. Hirose S. Mol. Cell. Biol. 1992; 12: 5667-5672Crossref PubMed Scopus (171) Google Scholar, 29.Wilson T.E. Fahrner T.J. Milbrandt J. Mol. Cell. Biol. 1993; 13: 5794-5804Crossref PubMed Scopus (356) Google Scholar).We show that the SF1/ELP transcription factor(s) is expressed not only in the cell lineages described above, but also in P19 EC cells, and its expression is down-regulated following RA treatment. SF1 activates theOct-3/4 promoter via two SF1-binding sites. Moreover, we point out a possible functional interaction of the SF1/ELP protein(s) with the RAR proteins to synergistically activate theOct-3/4 gene expression. The possible effect of SF-1/ELP on the Oct-3/4 gene and its synergism with members of the RAR family of transcription factors, adds sources of diversity to regulation of a RA-responsive gene.DISCUSSIONThe Oct-3/4 transcription factor is expressed in the earliest stages of embryogenesis (4.Okamoto K. Okazawa H. Okuda A. Sakai M. Muramatsu M. Hamada H. Cell. 1990; 60: 461-472Abstract Full Text PDF PubMed Scopus (607) Google Scholar, 5.Rosner M.H. Vigano M.A. Ozato K. Timmons P.M. Poirier F. Rigby P.W.J. Staudt L.M. Nature. 1990; 345: 686-692Crossref PubMed Scopus (755) Google Scholar, 6.Schöler H.R. Ruppert S. Suzuki N. Chowdhury K. Gruss P. Nature. 1990; 344: 435-439Crossref PubMed Scopus (591) Google Scholar, 7.Schöler H.R. Dressler G.R. Balling R. Rohdewohld H. Gruss P. EMBO J. 1990; 9: 2185-2195Crossref PubMed Scopus (492) Google Scholar), and is thus likely to play an important role in regulation of initial decisions in development (10.Nichols J. Zevnik B. Anastassiadis K. Niwa H. Klewe-Nebenius D. Chambers I. Schöler H. Smith A. Cell. 1998; 95: 379-391Abstract Full Text Full Text PDF PubMed Scopus (2639) Google Scholar). In order to better understand the molecular mechanisms that participate inOct-3/4 activation in pluripotent cells, we have examined the regulation of the Oct-3/4 promoter activity, in detail. The Oct-3/4 promoter is composed of multiple regulatory elements, including binding sites for Sp1, RAR:RXR heterodimers, COUP-TFI, and ARP-1 (14.Pikarsky E. Sharir H. Ben-Shushan E. Bergman Y. Mol. Cell. Biol. 1994; 14: 1026-1038Crossref PubMed Scopus (105) Google Scholar, 15.Schoorlemmer J. van Puijenbroek A. van den Eijnden M. Jonk L. Pals C. Kruijer W. Mol. Cell. Biol. 1994; 14: 1122-1136Crossref PubMed Scopus (91) Google Scholar, 16.Sylvester I. Schöler H.R. Nucleic Acids Res. 1994; 22: 901-911Crossref PubMed Scopus (73) Google Scholar). In this study we have provided proof that SF1-binding sites, and the SF1 protein play a role in up-regulatingOct-3/4 promoter activity. Furthermore, our data show that SF1 and RAR function cooperatively in transactivation of theOct-3/4 promoter. Interestingly, we have shown that SF1 is expressed in P19 EC cells, which also express the Oct-3/4gene, and expression of both transcription factors is down-regulated in EC cells which are induced to differentiate with RA. Considering these data, it seems likely that SF1 positively regulates Oct-3/4expression in EC cells.We have identified two novel putative SF1-binding sites in theOct-3/4 promoter: the proximal site, SF1(a), that is located within the previously identified RAREoct element, and the distal site, SF1(b), which is located between nucleotide −193 and −209 of theOct-3/4 promoter. The RAREoct is a compound element that harbors three direct repeats (R1-R3) of an AGGTCA-like consensus binding site for members of the RAR family of transcription factors, with 1- and 0-nucleotide spacers. The SF1-putative binding site encompasses the R3 and three adjacent nucleotides of the R2, whereas the RAR:RXR heterodimers bind to R1-R2 (16.Sylvester I. Schöler H.R. Nucleic Acids Res. 1994; 22: 901-911Crossref PubMed Scopus (73) Google Scholar). We have shown that SF1, which is expressed in P19 cells, binds to the RAREoct motif harboring the SF1(a) motif. Moreover, footprinting analysis of the 400-bpOct-3/4 promoter fragment, using COS-1/SF1 protein extracts revealed a protection pattern similar to that observed in our previous study, using cell extracts prepared from P19 cells (14.Pikarsky E. Sharir H. Ben-Shushan E. Bergman Y. Mol. Cell. Biol. 1994; 14: 1026-1038Crossref PubMed Scopus (105) Google Scholar). The undifferentiated P19 nuclear extracts protected a region between nucleotides −52 and −20 of the Oct-3/4 wild-type promoter. This region includes the Sp1, RAREoct, and SF1-binding sites. In contrast, extracts from P19/RA cells protected the region between nucleotides −52 and −34. This shorter region lacks the SF1-binding site. Introduction of mutations within the putative SF1(a)-binding site blunted the ability of SF1 to either bind or transactivate theOct-3/4 promoter. The distal SF1(b) sequence is a putative SF1-binding site, in a reverse orientation CCTGGAACT. Mutation analysis of the proximal and distal SF1 sites indicates that the proximal SF1(a) site is the main site through which SF1 affects the Oct-3/4promoter, as tested in P19 cells. Interestingly, numerous genes regulated by SF1 contain more than one SF1-binding site in their regulatory elements. The presence, in a promoter, of multiple binding sites for a single transcription factor may reflect different usage in various cellular backgrounds (53.Sugawara T. Holt J.A. Kiriakidou M. Strauss III, J.F. Biochemistry. 1996; 35: 9052-9059Crossref PubMed Scopus (236) Google Scholar, 54.Takayama K. Morohashi K.-i. Honda S.-i. Hara N. Omura T. J. Biochem. (Tokyo). 1994; 116: 193-203Crossref PubMed Scopus (54) Google Scholar, 55.Zhang P. Rodriguez H. Mellon S.H. Mol. Endocrinol. 1995; 9: 1571-1582Crossref PubMed Google Scholar).An Sp1 consensus binding site is located 5′ to the RAREoct motif. The proteins that take part in activating the Oct-3/4 promoter through the Sp1 site have not yet been identified, but it is likely that there could be unique Sp1 factors characterized by a cell lineage-specific rather than ubiquitous expression pattern. This Sp1 decamer sequence partially overlaps with the R1 sequence. Thus, the Sp1- and SF1-binding sites are closely located in theOct-3/4 promoter, and moreover, are both protected similarly using P19 (14.Pikarsky E. Sharir H. Ben-Shushan E. Bergman Y. Mol. Cell. Biol. 1994; 14: 1026-1038Crossref PubMed Scopus (105) Google Scholar) and COS/SF1 whole cell extracts. Proximal location of SF1 and Sp1 binding elements were observed in other genes as well (56.Hamann L. Bayer K.-U. Jensen K. Harbers K. Mol. Cell. Biol. 1994; 14: 5786-5793Crossref PubMed Scopus (16) Google Scholar, 57.Leone T.C. Cresci S. Carter M.E. Zhang Z. Lala D.S. Strauss A.W. Kelly D.P. J. Biol. Chem. 1995; 270: 16308-16314Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar, 58.Liu Z. Simpson E.R. Mol. Endocrinol. 1997; 11: 127-137Crossref PubMed Scopus (131) Google Scholar). An example for cooperative functional interactions between Sp1 and SF1 proteins have been shown in the transactivation of thecholesterol side chain cleavage enzyme (CYP11A) promoter (58.Liu Z. Simpson E.R. Mol. Endocrinol. 1997; 11: 127-137Crossref PubMed Scopus (131) Google Scholar). Furthermore, Sp1 and SF1 responsive elements have also been linked and involved in the cAMP-induced expression of various genes (53.Sugawara T. Holt J.A. Kiriakidou M. Strauss III, J.F. Biochemistry. 1996; 35: 9052-9059Crossref PubMed Scopus (236) Google Scholar, 55.Zhang P. Rodriguez H. Mellon S.H. Mol. Endocrinol. 1995; 9: 1571-1582Crossref PubMed Google Scholar, 58.Liu Z. Simpson E.R. Mol. Endocrinol. 1997; 11: 127-137Crossref PubMed Scopus (131) Google Scholar, 59.Carlone D.L. Richards J.S. Mol. Endocrinol. 1997; 11: 292-304PubMed Google Scholar). The cAMP-induced expression might involve cAMP-dependent protein kinase activation, and phosphorylation of the SF1 protein (60.Zhang P. Mellon S.H. Mol. Endocrinol. 1996; 10: 147-158Crossref PubMed Scopus (162) Google Scholar). Considering the fact that theOct-3/4 promoter sequence harbors SF1 and Sp1 neighboring sequences, combined with the data indicating a regulatory effect of cAMP on EC cells (61.Goldstein B. Rogelj S. Siegel S. Farmer S.R. Niles R.M. J. Cell. Physiol. 1990; 143: 205-212Crossref PubMed Scopus (5) Google Scholar, 62.Lenardo M.J. Staudt L. Robbins P. Kuang A. Mulligan R.C. Baltimore D. Science. 1989; 243: 544-546Crossref PubMed Scopus (97) Google Scholar, 63.Meier P. Koedood M. Philipp J. Fontana A. Mitchell P.J. Dev. Biol. 1995; 169: 1-14Crossref PubMed Scopus (58) Google Scholar), it seems likely that Oct-3/4promoter activity may be regulated through the cAMP signal transduction pathway.SF1 protein is involved in regulation of expression of genes in the hypothalamic-pituitary-gonadal axis and in the adrenal cortex. SF1 activates genes in steroidogenic cells (steroid hydroxylases, non-cytochrome P450 enzyme, steroidogenic acute regulatory protein, and ACTH receptor), in Sertoli cells (Müllerian-inhibiting substance andaromatase), and in the gonadotropes (α-subunit ofglycoproteins, β-subunit of leutinizing hormone, and the GnRH receptor, reviewed in Ref. 25.Parker K.L. Schimmer B.P. Endocr. Rev. 1997; 18: 361-377Crossref PubMed Scopus (556) Google Scholar). In this report we have demonstrated the presence, and indicated a possible functional role, of SF1 protein in a completely different cell lineage, i.e. the EC cells. To our knowledge, this is the first report of an EC-specific gene that is activated by SF1. Moreover, the kinetics of Oct-3/4 repression following RA treatment directly correlates with suppression of the SF1 transcripts. This direct correlation between Oct-3/4 and SF1 expression in EC cells, and down-regulation in RA-treated EC cells, as well as our binding and transfection experiments, may imply a functional relationship between SF1 and Oct-3/4. The DNA-binding domain (DBD) of the SF1 protein is necessary for SF1-mediated activation ofOct-3/4 gene expression. A similar requirement for the SF1 DBD for the activation of the P450ssc gene in ES cells and for differentiation of ES cells into steroidogenic cells, has also been demonstrated (64.Crawford P.A. Sadovsky Y. Milbrandt J. Mol. Cell. Biol. 1997; 17: 3997-4006Crossref PubMed Scopus (108) Google Scholar).On the basis of our previous experiments which implicate RAR:RXR heterodimers in activation of the Oct-3/4 promoter (17.Ben-Shushan E. Sharir H. Pikarsky E. Bergman Y. Mol. Cell. Biol. 1995; 15: 1034-1048Crossref PubMed Google Scholar), and in order to get a better understanding of the molecular mechanism underlying activation of the Oct-3/4 promoter via SF1, we have examined the possibility of a functional interaction between SF1 and RAR or RXR nuclear factors. We have shown that RAR acts in concert with SF1 to activate Oct-3/4 promoter expression. Co-transfections of both SF1 and RAR expression vectors into L cells clearly confirmed that the two transcription factors act in synergism on the Oct-3/4 promoter. This synergism was restricted to SF1 and RAR, since co-transfection of SF1 withRXRα, β, or γ had no effect on Oct-3/4expression. SF1 and RAR synergism requires the two respective binding sites, since disruption by site-directed mutagenesis of either site abolishes the synergism. This functional interaction also requires the SF1 DNA-binding domain. It has been previously shown that the RARs alone are inefficient DNA binders and require auxiliary nuclear proteins for effective interactions with responsive elements. The RXRs serve as such auxiliary proteins. It is possible that the SF1 protein is a similar auxiliary factor that facilitates the binding of RAR to DNA, improves the ability of RAR to interact with coactivators, or interferes with the ability of RAR to interact with corepressors. Unlike the RAR:RXR heterodimers that activate the Oct-3/4promoter in the presence of RA, the RAR and SF1 proteins synergistically activate the Oct-3/4 promoter in the absence of RA added to medium. Moreover, binding assays reveal that RA (10−4 to 10−7m) neither activated nor inhibited SF1·RAR complex formation (data not shown). In P19 cells Oct-3/4 expression is down-regulated following 24 h of RA treatment, whereas RAR:RXR expression is up-regulated by 3 h of treatment. Interestingly, 24 h of RA treatment results also in up-regulation of ARP-1 andCOUP-TFI orphan receptors which repress theOct-3/4 promoter (15.Schoorlemmer J. van Puijenbroek A. van den Eijnden M. Jonk L. Pals C. Kruijer W. Mol. Cell. Biol. 1994; 14: 1122-1136Crossref PubMed Scopus (91) Google Scholar, 16.Sylvester I. Schöler H.R. Nucleic Acids Res. 1994; 22: 901-911Crossref PubMed Scopus (73) Google Scholar, 17.Ben-Shushan E. Sharir H. Pikarsky E. Bergman Y. Mol. Cell. Biol. 1995; 15: 1034-1048Crossref PubMed Google Scholar). These orphan receptors bind the RAREoct site with a much higher affinity than the RAR:RXR and most probably also with a higher affinity than RAR and SF1. This high binding affinity provides the orphan receptors with the ability to compete and displace the activating receptors (RAR, RXR, and SF1) from the RAREoct site and subsequently to silence the Oct-3/4promoter.Although our studies clearly indicate that SF1 and RAR cooperate to synergistically activate the Oct-3/4 promoter, the nature of RAR-SF1 interaction is not yet clear. Our binding experiments show that SF1 and RAR form a novel complex which contains both transcription factors, on the RAREoct sequence. This complex could be formed through several molecular interactions, such as direct interactions between SF1 and RAR. Alternatively, since SF1 synergies with RAR and not with RXR, they may indirectly interact through a shared coactivator that is specific for this combination. Both were found to interact with multiple coactivators such as SRC-1, CBP, and p300 (65.Monté D. DeWitte F. Hum D.W. J. Biol. Chem. 1998; 273: 4585-4591Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar, 66.Ito M., Yu, R.N. Jameson J.L. Mol. Endocrinol. 1998; 12: 290-301Crossref PubMed Scopus (123) Google Scholar, 67.Perlmann T. Evans R.M. Cell. 1997; 90: 391-397Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar). These two modes of interactions (direct or through coactivators) are not mutually exclusive. In addition, SF1 and RAR can bind to their adjacent sites cooperatively, binding of one transcription factor altering the DNA conformation in a way which increases the local accessibility for the second transcription factor. The effect of SF1 alone onOct-3/4 promoter activity, although very consistent, is moderate and is enhanced considerably in the presence of RAR. It is possible that tissue-specific expression of genes regulated by SF1 could be reinforced by the presence of other transcription factors expressed in the tissue and act in synergism with SF1. Thus, the ability of RAR to synergize with SF1 in enhancing Oct-3/4 expression, may also contribute to restriction of the activation ofOct-3/4 in appropriate cell types where both transcription factors are expressed.Similarly to NGFI-B, NURR1, and thyroid hormone, that bind both as monomers or as dimers (reviewed in Refs. 20.Chambon P. FASEB J. 1996; 10: 940-954Crossref PubMed Scopus (2587) Google Scholar and 68.Perlmann T. Lottie J. Genes Dev. 1995; 9: 769-782Crossref PubMed Scopus (472) Google Scholar), SF1 may also belong to this category of monomer/dimer binding receptors. In fact, several studies have described the effect of protein-protein interactions in SF1-dependent transcription. It has been shown that co-transfection of the zinc finger NGFI-A (Egr-1) and SF1 transcription factors led to synergistic activation of theLHβ promoter (69.Dorn C. Ou Q. Svaren J. Crawford P.A. Sadovsky Y. J. Biol. Chem. 1999; 274: 13870-13876Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar, 70.Halvorson L.M. Kaiser U.B. Chin W.W. Mol. Endocrinol. 1999; 13: 106-116Crossref PubMed Scopus (93) Google Scholar, 71.Tremblay J.J. Drouin J. Mol. Cell. Biol. 1999; 19: 2567-2576Crossref PubMed Google Scholar, 72.Lee S.L. Sadovsky Y. Swirnoff A.H. Polish J.A. Goda P. Gavrilina G. Milbrandt J. Science. 1996; 273: 1219-1221Crossref PubMed Scopus (434) Google Scholar). This enhancement ofLHβ transcription most probably results from a direct interaction between Egr-1 and SF1 (71.Tremblay J.J. Drouin J. Mol. Cell. Biol. 1999; 19: 2567-2576Crossref PubMed Google Scholar). Similarly, estradiol receptor and SF1 have been found to synergistically regulate the salmon gonadotropin II gene (sGTHIIβ) in the presence of estradiol (73.Le Dréan Y. Liu D. Wong A.O.L. Xiong F. Hew C.L. Mol. Endocrinol. 1996; 10: 217-229PubMed Google Scholar). In addition, using the mammalian two-hybrid system, Sp1 and SF1 have been shown to functionally collaborate in the transactivation of the bovine CYP11A (58.Liu Z. Simpson E.R. Mol. Endocrinol. 1997; 11: 127-137Crossref PubMed Scopus (131) Google Scholar). SF1 was found to associate and sinergize also with Wilms' tumor −1 and SOX9 to promoteMüllerian inhibiting substance andanti-Müllerian hormone expression, respectively (74.Nachtigal M.W. Hirokawa Y. Enyeart-Van Houten D.L. Flanagan J.N. Hammer G.D. Ingraham H.A. Cell. 1998; 93: 445-454Abstract Full Text Full Text PDF P" @default.
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• W2067207360 title "Synergy of SF1 and RAR in Activation of Oct-3/4Promoter" @default.
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