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• W2101002008 abstract "The nuclear factor of activated T cells (NFAT) group of transcription factors regulates gene expression in immune and non-immune cells. NFAT-mediated gene transcription is orchestrated, in part, by formation of a composite regulatory element. Here we demonstrate that NFAT interacts with transcription factor CCAAT/enhancer-binding protein (C/EBP) to form a composite enhancer complex, to potentiate expression of the peroxisome proliferator-activated receptor-γ2 gene. Formation of a ternary NFAT·C/EBP·DNA complex is required for the transcriptional cooperation. A similar NFAT·C/EBP composite element is found in the regulatory region of the insulin-like growth factor 2, angiotensin-converting enzyme homolog, and transcription factor POU4F3 genes. Thus, the NFAT·C/EBP composite element represents a novel regulatory enhancer to direct NFAT-mediated gene transcription. The nuclear factor of activated T cells (NFAT) group of transcription factors regulates gene expression in immune and non-immune cells. NFAT-mediated gene transcription is orchestrated, in part, by formation of a composite regulatory element. Here we demonstrate that NFAT interacts with transcription factor CCAAT/enhancer-binding protein (C/EBP) to form a composite enhancer complex, to potentiate expression of the peroxisome proliferator-activated receptor-γ2 gene. Formation of a ternary NFAT·C/EBP·DNA complex is required for the transcriptional cooperation. A similar NFAT·C/EBP composite element is found in the regulatory region of the insulin-like growth factor 2, angiotensin-converting enzyme homolog, and transcription factor POU4F3 genes. Thus, the NFAT·C/EBP composite element represents a novel regulatory enhancer to direct NFAT-mediated gene transcription. nuclear factor of activated T cells CCAAT/enhancer-binding protein antigen receptor-responsive element interleukin phorbol 12-myristate 13-acetate insulin-like growth factor 2 peroxisome proliferator-activated receptor-γ2 angiotensin-converting enzyme homolog basic leucine zipper DNase I-hypersensitive sites baby hamster kidney glutathione S-transferase Nuclear factor of activated T cells (NFAT)1 was first identified as an important regulator for cytokine gene expression (1Rao A. Luo C. Hogan P.G. Annu. Rev. Immunol. 1997; 15: 707-747Crossref PubMed Scopus (2203) Google Scholar, 2Crabtree G.R. J. Biol. Chem. 2001; 276: 2313-2316Abstract Full Text Full Text PDF PubMed Scopus (377) Google Scholar). Subsequent isolation of cDNAs reveals a broad distribution of NFAT in multiple tissues. For example, NFAT regulates expression of type 1 inositol 1,4,5-trisphosphate receptor and is implicated in learning and memory (3Graef I.A. Mermelstein P.G. Stankunas K. Neilson J.R. Deisseroth K. Tsien R.W. Crabtree G.R. Nature. 1999; 401: 703-708Crossref PubMed Scopus (451) Google Scholar). NFAT regulates expression of b-type natriuretic peptide during cardiac hypertrophy (4Molkentin J.D. Lu J.R. Antos C.L. Markham B. Richardson J. Robbins J. Grant S.R. Olson E.N. Cell. 1998; 93: 215-228Abstract Full Text Full Text PDF PubMed Scopus (2191) Google Scholar). NFAT also modulates skeletal muscle fiber type by directing selective gene expression in slow oxidative myofibers (e.g. myoglobin gene and slow fiber-specific troponin I gene) (5Chin E.R. Olson E.N. Richardson J.A. Yang Q. Humphries C. Shelton J.M. Wu H. Zhu W. Bassel-Duby R. Williams R.S. Genes Dev. 1998; 12: 2499-2509Crossref PubMed Scopus (824) Google Scholar). NFAT also regulates expression of fatty acid-binding protein and transcription factor peroxisome proliferator-activated receptor-γ2 (PPARγ2) during adipogenesis (6Ho I.C. Kim J.H. Rooney J.W. Spiegelman B.M. Glimcher L.H. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 15537-15541Crossref PubMed Scopus (97) Google Scholar,7Yang T.T. Xiong Q. Enslen H. Davis R.J. Chow C.W. Mol. Cell. Biol. 2002; 22: 3892-3904Crossref PubMed Scopus (145) Google Scholar). Recent microarray analyses have further revealed a wealth of novel NFAT target genes (8Macian F. Garcia-Cozar F. Im S.H. Horton H.F. Byrne M.C. Rao A. Cell. 2002; 109: 719-731Abstract Full Text Full Text PDF PubMed Scopus (548) Google Scholar, 9Graef I.A. Chen F. Chen L. Kuo A. Crabtree G.R. Cell. 2001; 105: 863-875Abstract Full Text Full Text PDF PubMed Scopus (354) Google Scholar, 10Feske S. Giltnane J. Dolmetsch R. Staudt L.M. Rao A. Nat. Immunol. 2001; 2: 316-324Crossref PubMed Scopus (495) Google Scholar). As elucidation of the physiological functions of NFAT progresses, many more novel NFAT target genes will be identified. However, the molecular basis that governs the expression of these NFAT target genes remains to be determined.NFAT interacts with transcription factor AP-1 (Fos and Jun proteins) to form a cooperative composite enhancer (NFAT·AP-1) and to regulate expression of many cytokine genes (11Macian F. Lopez-Rodriguez C. Rao A. Oncogene. 2001; 20: 2476-2489Crossref PubMed Scopus (610) Google Scholar). The cooperative induction is mediated, in part, by protein-protein and protein-DNA interactions. For example, the well characterized antigen receptor-responsive element (ARRE) from the interleukin (IL)-2 gene contains binding sites for NFAT and AP-1 (12Northrop J.P. Ullman K.S. Crabtree G.R. J. Biol. Chem. 1993; 268: 2917-2923Abstract Full Text PDF PubMed Google Scholar, 13Durand D.B. Shaw J.P. Bush M.R. Replogle R.E. Belagaje R. Crabtree G.R. Mol. Cell. Biol. 1988; 8: 1715-1724Crossref PubMed Scopus (374) Google Scholar, 14Jain J. McCaffrey P.G. Valge-Archer V.E. Rao A. Nature. 1992; 356: 801-804Crossref PubMed Scopus (427) Google Scholar). The DNA binding domains of NFAT and AP-1 are required for the cooperative interaction on the ARRE enhancer (15Macian F. Garcia-Rodriguez C. Rao A. EMBO J. 2000; 19: 4783-4795Crossref PubMed Scopus (258) Google Scholar, 16Luo C. Burgeon E. Rao A. J. Exp. Med. 1996; 184: 141-147Crossref PubMed Scopus (86) Google Scholar). Structural analysis reveals multiple contacts between the DNA binding domains of NFAT and AP-1 (17Sun L.J. Peterson B.R. Verdine G.L. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 4919-4924Crossref PubMed Scopus (42) Google Scholar, 18Zhou P. Sun L.J. Dotsch V. Wagner G. Verdine G.L. Cell. 1998; 92: 687-696Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar, 19Chen L. Glover J.N. Hogan P.G. Rao A. Harrison S.C. Nature. 1998; 392: 42-48Crossref PubMed Scopus (410) Google Scholar). Conserved residues are responsible for the protein-protein and protein-DNA interactions. Thus, intimate associations between NFAT, AP-1, and DNA are necessary for the transcription cooperation of the IL-2 gene.Transcription factor peroxisome proliferator-activated receptor-γ2 (PPARγ2) plays an important role in adipogenesis (20MacDougald O.A. Lane M.D. Annu. Rev. Biochem. 1995; 64: 345-373Crossref PubMed Scopus (933) Google Scholar, 21Cowherd R.M. Lyle R.E. McGehee Jr., R.E. Semin. Cell Dev. Biol. 1999; 10: 3-10Crossref PubMed Scopus (235) Google Scholar, 22Tontonoz P. Hu E. Spiegelman B.M. Curr. Opin. Genet. & Dev. 1995; 5: 571-576Crossref PubMed Scopus (402) Google Scholar, 23Rosen E.D. Spiegelman B.M. J. Biol. Chem. 2001; 276: 37731-37734Abstract Full Text Full Text PDF PubMed Scopus (1068) Google Scholar). Multiple transcription factors have been shown to regulate the PPARγ2 gene expression. For example, members of the CCAAT/enhancer-binding protein (C/EBP) family induce expression of PPARγ2 during adipocyte differentiation (24Wu Z. Bucher N.L. Farmer S.R. Mol. Cell. Biol. 1996; 16: 4128-4136Crossref PubMed Google Scholar, 25Wu Z. Xie Y. Bucher N.L. Farmer S.R. Genes Dev. 1995; 9: 2350-2363Crossref PubMed Scopus (475) Google Scholar). Several C/EBP-binding elements have been identified on the PPARγ2 gene promoter (26Zhu Y. Qi C. Korenberg J.R. Chen X.N. Noya D. Rao M.S. Reddy J.K. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 7921-7925Crossref PubMed Scopus (598) Google Scholar, 27Fajas L. Auboeuf D. Raspe E. Schoonjans K. Lefebvre A.M. Saladin R. Najib J. Laville M. Fruchart J.C. Deeb S. Vidal-Puig A. Flier J. Briggs M.R. Staels B. Vidal H. Auwerx J. J. Biol. Chem. 1997; 272: 18779-18789Abstract Full Text Full Text PDF PubMed Scopus (1075) Google Scholar, 28Yun Z. Maecker H.L. Johnson R.S. Giaccia A.J. Dev. Cell. 2002; 2: 331-341Abstract Full Text Full Text PDF PubMed Scopus (377) Google Scholar, 29Shi X.M. Blair H.C. Yang X. McDonald J.M. Cao X. J. Cell. Biochem. 2000; 76: 518-527Crossref PubMed Scopus (101) Google Scholar, 30Elberg G. Gimble J.M. Tsai S.Y. J. Biol. Chem. 2000; 275: 27815-27822Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar). Recently, two distinctive NFAT-binding sites (proximal and distal) are identified on the PPARγ2 gene (7Yang T.T. Xiong Q. Enslen H. Davis R.J. Chow C.W. Mol. Cell. Biol. 2002; 22: 3892-3904Crossref PubMed Scopus (145) Google Scholar). The NFAT- and C/EBP-binding sites are located in the immediate upstream regulatory region of the PPARγ2 promoter. Whether NFAT cooperates with C/EBP to regulate the PPARγ2 gene expression remains uncertain.The significance of the PPARγ2 NFAT regulatory elements is further implicated by recent DNase I-hypersensitive site studies (31Ren D. Collingwood T.N. Rebar E.J. Wolffe A.P. Camp H.S. Genes Dev. 2002; 16: 27-32Crossref PubMed Scopus (302) Google Scholar). Two DNase I-hypersensitive sites (DHS1 and DHS2) are found in the PPARγ2 gene. DNase I-hypersensitive sites represent regions that are “accessible” for transcription factor binding in the nucleosome-packed chromatin (32Veenstra G.J. Wolffe A.P. Trends Biochem. Sci. 2001; 26: 665-671Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar, 33Felsenfeld G. Boyes J. Chung J. Clark D. Studitsky V. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 9384-9388Crossref PubMed Scopus (156) Google Scholar, 34Elgin S.C. Cell. 1981; 27: 413-415Abstract Full Text PDF PubMed Scopus (243) Google Scholar, 35Krebs J.E. Peterson C.L. Crit. Rev. Eukaryotic Gene Expr. 2000; 10: 1-12Crossref PubMed Google Scholar). Binding of transcription factors to the DNase I-hypersensitive sites may facilitate chromatin rearrangement and/or transcriptional activation of promoters that are actively engaged in gene expression. Thus, identification of proteins that bind to DNase I-hypersensitive sites is important to understand transcriptional regulation. The PPARγ2 distal NFAT element is located between the DHS1 and the DHS2 DNase I-hypersensitive site. The PPARγ2-proximal NFAT element is located within DHS1. The proximity of these NFAT elements to the DNase I-hypersensitive sites suggests that understanding the molecular basis of NFAT-mediated transcription will shed new light on the regulation of PPARγ2 gene.The purpose of this study is to examine the molecular basis of NFAT-mediated gene expression. We report that NFAT cooperates with C/EBP to regulate PPARγ2 gene expression. The transcription cooperation is mediated, in part, by the formation of a composite NFAT·C/EBP complex on the PPARγ2-proximal NFAT element. Promoter analysis reveals that a similar NFAT·C/EBP composite element regulates transcription of insulin-like growth factor 2, angiotensin-converting enzyme homolog, and transcription factor POU4F3 genes. Thus, the NFAT·C/EBP complex represents a novel composite regulatory element to direct NFAT-mediated gene expression. Nuclear factor of activated T cells (NFAT)1 was first identified as an important regulator for cytokine gene expression (1Rao A. Luo C. Hogan P.G. Annu. Rev. Immunol. 1997; 15: 707-747Crossref PubMed Scopus (2203) Google Scholar, 2Crabtree G.R. J. Biol. Chem. 2001; 276: 2313-2316Abstract Full Text Full Text PDF PubMed Scopus (377) Google Scholar). Subsequent isolation of cDNAs reveals a broad distribution of NFAT in multiple tissues. For example, NFAT regulates expression of type 1 inositol 1,4,5-trisphosphate receptor and is implicated in learning and memory (3Graef I.A. Mermelstein P.G. Stankunas K. Neilson J.R. Deisseroth K. Tsien R.W. Crabtree G.R. Nature. 1999; 401: 703-708Crossref PubMed Scopus (451) Google Scholar). NFAT regulates expression of b-type natriuretic peptide during cardiac hypertrophy (4Molkentin J.D. Lu J.R. Antos C.L. Markham B. Richardson J. Robbins J. Grant S.R. Olson E.N. Cell. 1998; 93: 215-228Abstract Full Text Full Text PDF PubMed Scopus (2191) Google Scholar). NFAT also modulates skeletal muscle fiber type by directing selective gene expression in slow oxidative myofibers (e.g. myoglobin gene and slow fiber-specific troponin I gene) (5Chin E.R. Olson E.N. Richardson J.A. Yang Q. Humphries C. Shelton J.M. Wu H. Zhu W. Bassel-Duby R. Williams R.S. Genes Dev. 1998; 12: 2499-2509Crossref PubMed Scopus (824) Google Scholar). NFAT also regulates expression of fatty acid-binding protein and transcription factor peroxisome proliferator-activated receptor-γ2 (PPARγ2) during adipogenesis (6Ho I.C. Kim J.H. Rooney J.W. Spiegelman B.M. Glimcher L.H. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 15537-15541Crossref PubMed Scopus (97) Google Scholar,7Yang T.T. Xiong Q. Enslen H. Davis R.J. Chow C.W. Mol. Cell. Biol. 2002; 22: 3892-3904Crossref PubMed Scopus (145) Google Scholar). Recent microarray analyses have further revealed a wealth of novel NFAT target genes (8Macian F. Garcia-Cozar F. Im S.H. Horton H.F. Byrne M.C. Rao A. Cell. 2002; 109: 719-731Abstract Full Text Full Text PDF PubMed Scopus (548) Google Scholar, 9Graef I.A. Chen F. Chen L. Kuo A. Crabtree G.R. Cell. 2001; 105: 863-875Abstract Full Text Full Text PDF PubMed Scopus (354) Google Scholar, 10Feske S. Giltnane J. Dolmetsch R. Staudt L.M. Rao A. Nat. Immunol. 2001; 2: 316-324Crossref PubMed Scopus (495) Google Scholar). As elucidation of the physiological functions of NFAT progresses, many more novel NFAT target genes will be identified. However, the molecular basis that governs the expression of these NFAT target genes remains to be determined. NFAT interacts with transcription factor AP-1 (Fos and Jun proteins) to form a cooperative composite enhancer (NFAT·AP-1) and to regulate expression of many cytokine genes (11Macian F. Lopez-Rodriguez C. Rao A. Oncogene. 2001; 20: 2476-2489Crossref PubMed Scopus (610) Google Scholar). The cooperative induction is mediated, in part, by protein-protein and protein-DNA interactions. For example, the well characterized antigen receptor-responsive element (ARRE) from the interleukin (IL)-2 gene contains binding sites for NFAT and AP-1 (12Northrop J.P. Ullman K.S. Crabtree G.R. J. Biol. Chem. 1993; 268: 2917-2923Abstract Full Text PDF PubMed Google Scholar, 13Durand D.B. Shaw J.P. Bush M.R. Replogle R.E. Belagaje R. Crabtree G.R. Mol. Cell. Biol. 1988; 8: 1715-1724Crossref PubMed Scopus (374) Google Scholar, 14Jain J. McCaffrey P.G. Valge-Archer V.E. Rao A. Nature. 1992; 356: 801-804Crossref PubMed Scopus (427) Google Scholar). The DNA binding domains of NFAT and AP-1 are required for the cooperative interaction on the ARRE enhancer (15Macian F. Garcia-Rodriguez C. Rao A. EMBO J. 2000; 19: 4783-4795Crossref PubMed Scopus (258) Google Scholar, 16Luo C. Burgeon E. Rao A. J. Exp. Med. 1996; 184: 141-147Crossref PubMed Scopus (86) Google Scholar). Structural analysis reveals multiple contacts between the DNA binding domains of NFAT and AP-1 (17Sun L.J. Peterson B.R. Verdine G.L. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 4919-4924Crossref PubMed Scopus (42) Google Scholar, 18Zhou P. Sun L.J. Dotsch V. Wagner G. Verdine G.L. Cell. 1998; 92: 687-696Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar, 19Chen L. Glover J.N. Hogan P.G. Rao A. Harrison S.C. Nature. 1998; 392: 42-48Crossref PubMed Scopus (410) Google Scholar). Conserved residues are responsible for the protein-protein and protein-DNA interactions. Thus, intimate associations between NFAT, AP-1, and DNA are necessary for the transcription cooperation of the IL-2 gene. Transcription factor peroxisome proliferator-activated receptor-γ2 (PPARγ2) plays an important role in adipogenesis (20MacDougald O.A. Lane M.D. Annu. Rev. Biochem. 1995; 64: 345-373Crossref PubMed Scopus (933) Google Scholar, 21Cowherd R.M. Lyle R.E. McGehee Jr., R.E. Semin. Cell Dev. Biol. 1999; 10: 3-10Crossref PubMed Scopus (235) Google Scholar, 22Tontonoz P. Hu E. Spiegelman B.M. Curr. Opin. Genet. & Dev. 1995; 5: 571-576Crossref PubMed Scopus (402) Google Scholar, 23Rosen E.D. Spiegelman B.M. J. Biol. Chem. 2001; 276: 37731-37734Abstract Full Text Full Text PDF PubMed Scopus (1068) Google Scholar). Multiple transcription factors have been shown to regulate the PPARγ2 gene expression. For example, members of the CCAAT/enhancer-binding protein (C/EBP) family induce expression of PPARγ2 during adipocyte differentiation (24Wu Z. Bucher N.L. Farmer S.R. Mol. Cell. Biol. 1996; 16: 4128-4136Crossref PubMed Google Scholar, 25Wu Z. Xie Y. Bucher N.L. Farmer S.R. Genes Dev. 1995; 9: 2350-2363Crossref PubMed Scopus (475) Google Scholar). Several C/EBP-binding elements have been identified on the PPARγ2 gene promoter (26Zhu Y. Qi C. Korenberg J.R. Chen X.N. Noya D. Rao M.S. Reddy J.K. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 7921-7925Crossref PubMed Scopus (598) Google Scholar, 27Fajas L. Auboeuf D. Raspe E. Schoonjans K. Lefebvre A.M. Saladin R. Najib J. Laville M. Fruchart J.C. Deeb S. Vidal-Puig A. Flier J. Briggs M.R. Staels B. Vidal H. Auwerx J. J. Biol. Chem. 1997; 272: 18779-18789Abstract Full Text Full Text PDF PubMed Scopus (1075) Google Scholar, 28Yun Z. Maecker H.L. Johnson R.S. Giaccia A.J. Dev. Cell. 2002; 2: 331-341Abstract Full Text Full Text PDF PubMed Scopus (377) Google Scholar, 29Shi X.M. Blair H.C. Yang X. McDonald J.M. Cao X. J. Cell. Biochem. 2000; 76: 518-527Crossref PubMed Scopus (101) Google Scholar, 30Elberg G. Gimble J.M. Tsai S.Y. J. Biol. Chem. 2000; 275: 27815-27822Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar). Recently, two distinctive NFAT-binding sites (proximal and distal) are identified on the PPARγ2 gene (7Yang T.T. Xiong Q. Enslen H. Davis R.J. Chow C.W. Mol. Cell. Biol. 2002; 22: 3892-3904Crossref PubMed Scopus (145) Google Scholar). The NFAT- and C/EBP-binding sites are located in the immediate upstream regulatory region of the PPARγ2 promoter. Whether NFAT cooperates with C/EBP to regulate the PPARγ2 gene expression remains uncertain. The significance of the PPARγ2 NFAT regulatory elements is further implicated by recent DNase I-hypersensitive site studies (31Ren D. Collingwood T.N. Rebar E.J. Wolffe A.P. Camp H.S. Genes Dev. 2002; 16: 27-32Crossref PubMed Scopus (302) Google Scholar). Two DNase I-hypersensitive sites (DHS1 and DHS2) are found in the PPARγ2 gene. DNase I-hypersensitive sites represent regions that are “accessible” for transcription factor binding in the nucleosome-packed chromatin (32Veenstra G.J. Wolffe A.P. Trends Biochem. Sci. 2001; 26: 665-671Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar, 33Felsenfeld G. Boyes J. Chung J. Clark D. Studitsky V. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 9384-9388Crossref PubMed Scopus (156) Google Scholar, 34Elgin S.C. Cell. 1981; 27: 413-415Abstract Full Text PDF PubMed Scopus (243) Google Scholar, 35Krebs J.E. Peterson C.L. Crit. Rev. Eukaryotic Gene Expr. 2000; 10: 1-12Crossref PubMed Google Scholar). Binding of transcription factors to the DNase I-hypersensitive sites may facilitate chromatin rearrangement and/or transcriptional activation of promoters that are actively engaged in gene expression. Thus, identification of proteins that bind to DNase I-hypersensitive sites is important to understand transcriptional regulation. The PPARγ2 distal NFAT element is located between the DHS1 and the DHS2 DNase I-hypersensitive site. The PPARγ2-proximal NFAT element is located within DHS1. The proximity of these NFAT elements to the DNase I-hypersensitive sites suggests that understanding the molecular basis of NFAT-mediated transcription will shed new light on the regulation of PPARγ2 gene. The purpose of this study is to examine the molecular basis of NFAT-mediated gene expression. We report that NFAT cooperates with C/EBP to regulate PPARγ2 gene expression. The transcription cooperation is mediated, in part, by the formation of a composite NFAT·C/EBP complex on the PPARγ2-proximal NFAT element. Promoter analysis reveals that a similar NFAT·C/EBP composite element regulates transcription of insulin-like growth factor 2, angiotensin-converting enzyme homolog, and transcription factor POU4F3 genes. Thus, the NFAT·C/EBP complex represents a novel composite regulatory element to direct NFAT-mediated gene expression. We thank Drs. M. P. Clark, T. Hoey, P. F. Johnson, T. Soderling, and B. M. Spiegelman for providing reagents. We thank Drs. R. J. Davis, M. Rincón, and C. S. Rubin for their critical reading of the manuscript." @default.
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• W2101002008 title "Transcription Cooperation by NFAT·C/EBP Composite Enhancer Complex" @default.
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