GATA-6 and Thyroid Transcription Factor-1 Directly Interact and Regulate Surfactant Protein-C Gene Expression

GATA-6, a member of the GATA family of zinc finger domain containing transcription factors, is expressed in endodermally derived tissues including the lung, where GATA-6 influences the transcription of target genes, TTF-1, and surfactant proteins. Whereas GATA-6 did not directly alter expression ofsp-C constructs in HeLa cells, GATA-6 synergistically activated sp-C gene transcription when co-expressed with TTF-1, supporting the concept that GATA-6 and TTF-1 might directly interact to influence target gene expression. GST-GATA-6 directly co-precipitated with TTF-1 after in vitrotranslation and directly interacted with the TTF-1-binding element in the sp-C promoter. Binding of TTF-1 to GATA-6 required the homeodomain of TTF-1, but optimal interactions with GATA-6 required the homeodomain and either carboxyl- or amino-terminal domains of TTF-1. Interactions between TTF-1 and GATA-6 required the amino-terminal and zinc finger domains of GATA-6. Although GATA-4 also interacted with TTF-1 in two-hybrid assays, GATA-4 was not as active as GATA-6 in the activation of the sp-C promoter with TTF-1. Deletion and substitution mutations between GATA-4 and GATA-6 demonstrated that the carboxyl-terminal zinc finger domain of GATA-6 contributed to its synergistic activation of the sp-C promoter with TTF-1. GATA-6 influenced the activity of the sp-C promoter, binding and acting synergistically with TTF-1. GATA-6, a member of the GATA family of zinc finger domain containing transcription factors, is expressed in endodermally derived tissues including the lung, where GATA-6 influences the transcription of target genes, TTF-1, and surfactant proteins. Whereas GATA-6 did not directly alter expression ofsp-C constructs in HeLa cells, GATA-6 synergistically activated sp-C gene transcription when co-expressed with TTF-1, supporting the concept that GATA-6 and TTF-1 might directly interact to influence target gene expression. GST-GATA-6 directly co-precipitated with TTF-1 after in vitrotranslation and directly interacted with the TTF-1-binding element in the sp-C promoter. Binding of TTF-1 to GATA-6 required the homeodomain of TTF-1, but optimal interactions with GATA-6 required the homeodomain and either carboxyl- or amino-terminal domains of TTF-1. Interactions between TTF-1 and GATA-6 required the amino-terminal and zinc finger domains of GATA-6. Although GATA-4 also interacted with TTF-1 in two-hybrid assays, GATA-4 was not as active as GATA-6 in the activation of the sp-C promoter with TTF-1. Deletion and substitution mutations between GATA-4 and GATA-6 demonstrated that the carboxyl-terminal zinc finger domain of GATA-6 contributed to its synergistic activation of the sp-C promoter with TTF-1. GATA-6 influenced the activity of the sp-C promoter, binding and acting synergistically with TTF-1. Clara cell secretory protein thyroid transcription factor-1 retinoic acid receptors electrophoretic mobility shift assays analysis of variance glutathione S-transferase nuclear extract murine lung epithelial postcoitum hemagglutinin Lung structure and respiratory epithelial cell gene expression are determined by the actions of a number of nuclear transcription factors, including members of homeodomain, Forkhead, and zinc finger families of proteins (1Costa R.H. Kalinichenko V.V. Lim L. Am. J. Physiol. 2001; 280: L823-L838Crossref PubMed Google Scholar, 2Perl A.K. Whitsett J.A. Clin. Genet. 1999; 56: 14-27Crossref PubMed Scopus (124) Google Scholar). Members of these families of transcription factors are expressed in the foregut endoderm during lung morphogenesis and in subsets of respiratory epithelial cells later in development, where they influence the expression of genes selectively expressed in the lung, including surfactant proteins SP-A, -B, -C, and Clara cell secretory protein (CCSP)1(3Di Bohinski R.J. Lauro R. Whitsett J.A. Mol. Cell. Biol. 1994; 14: 5671-5681Crossref PubMed Scopus (484) Google Scholar, 4Bruno M.D. Bohinski R.J. Huelsman K.M. Whitsett J.A. Korfhagen T.R. J. Biol. Chem. 1995; 270: 6531-6536Abstract Full Text Full Text PDF PubMed Scopus (238) Google Scholar, 5Bruno M.D. Korfhagen T.R. Liu C. Morrisey E.E. Whitsett J.A. J. Biol. Chem. 2000; 275: 1043-1049Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar, 6Kelly S.E. Bachurski C.J. Burhans M.S. Glasser S.W. J. Biol. Chem. 1996; 271: 6881-6888Abstract Full Text Full Text PDF PubMed Scopus (216) Google Scholar, 7Tichelaar J.W. Lim L. Costa R.H. Whitsett J.A. Dev. Biol. 1999; 213: 405-417Crossref PubMed Scopus (63) Google Scholar, 8Zhang L. Whitsett J.A. Stripp B.R. Biochim. Biophys. Acta. 1997; 1350: 359-367Crossref PubMed Scopus (126) Google Scholar, 9Zhou L. Dey C.R. Wert S.E. Yan C. Costa R.H. Whitsett J.A. Dev. Dyn. 1997; 210: 305-314Crossref PubMed Scopus (64) Google Scholar). Thyroid transcription factor-1 (TTF-1), a member of the family of homeodomain-containing transcription factors, plays a critical role in both lung morphogenesis and in respiratory epithelial cell gene expression. TTF-1 is required for the transcription of surfactant proteins and for the formation and differentiation of epithelial cells lining the peripheral respiratory tract (3Di Bohinski R.J. Lauro R. Whitsett J.A. Mol. Cell. Biol. 1994; 14: 5671-5681Crossref PubMed Scopus (484) Google Scholar, 4Bruno M.D. Bohinski R.J. Huelsman K.M. Whitsett J.A. Korfhagen T.R. J. Biol. Chem. 1995; 270: 6531-6536Abstract Full Text Full Text PDF PubMed Scopus (238) Google Scholar, 6Kelly S.E. Bachurski C.J. Burhans M.S. Glasser S.W. J. Biol. Chem. 1996; 271: 6881-6888Abstract Full Text Full Text PDF PubMed Scopus (216) Google Scholar, 8Zhang L. Whitsett J.A. Stripp B.R. Biochim. Biophys. Acta. 1997; 1350: 359-367Crossref PubMed Scopus (126) Google Scholar, 10Minoo P. Su G. Drum H. Bringas P. Kimura S. Dev. Biol. 1999; 209: 60-71Crossref PubMed Scopus (353) Google Scholar, 11Yuan C. Kimura S. B.R. P. Dev. Dyn. 2000; PubMed Scopus Google Scholar). TTF-1, also is a member of the family of transcription factors that element the containing in of target genes G. L. S. S. S. Lauro R. 1994; PubMed Scopus Google Scholar). and in the surfactant protein and gene are required for the activity of the surfactant TTF-1 directly gene expression when expressed in epithelial is that TTF-1 with a number of transcription factors, of target TTF-1 with retinoic acid receptors and C. J. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google nuclear family members Bachurski C.J. Yan C. Whitsett J.A. Am. J. Physiol. 1999; Google and Am. J. Mol. Biol. 2001; PubMed Scopus Google Scholar). the and of target genes, TTF-1 directly or with these factors to gene expression. these interactions are by interactions the transcription factors, or in with transcription factors, is is a member of a family of nuclear transcription factors that to GATA containing zinc finger GATA family of proteins as and are in cell differentiation and gene and and influence endodermally and derived including lung and R. A.K. J. 1997; Full Text PDF PubMed Scopus Google Scholar, Mol. Cell. Biol. PubMed Scopus Google Scholar, S. Dev. Genet. PubMed Scopus Google Scholar, C. C. J. Biol. Chem. 1994; Full Text PDF PubMed Google Scholar, E.E. M.S. Dev. Biol. 1996; PubMed Scopus Google Scholar, 1999; Google Scholar). GATA-6 was in the and lung in the E.E. M.S. Dev. Biol. 1996; PubMed Scopus Google Scholar). GATA family members the domain and binding the of GATA family members is to by with transcription factors or to transcription of target genes R. R.J. J. 1997; PubMed Scopus Google Scholar, J. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, C.J. J. R. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, R.J. Mol. Cell. Biol. PubMed Scopus Google Scholar, J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar). in GATA-4 is co-expressed with in cells R.J. Mol. Cell. Biol. PubMed Scopus Google and is that but not GATA-6 or directly and M.D. Whitsett J.A. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google GATA-6 was to to in the of the gene expression of GATA-6 and TTF-1 in the lung and with the of expression of surfactant including L. Lim L. Costa R.H. Whitsett J.A. J. 1996; PubMed Scopus Google Scholar). S.W. Burhans M.S. Korfhagen T.R. Whitsett J.A. S. 2001; PubMed Scopus (238) Google demonstrated the critical role of surfactant in surfactant and of lung GATA-6 gene transcription in M.D. Korfhagen T.R. Liu C. Morrisey E.E. Whitsett J.A. J. Biol. Chem. 2000; 275: 1043-1049Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar). was to GATA-6 influences the activity of the surfactant promoter and GATA-6 and TTF-1 might directly interact interactions between GATA-6 and TTF-1 and synergistic the transcription of the and TTF-1 synergistically the activity of the surfactant protein promoter. of the transcription factors was by and two-hybrid binding was the homeodomain of TTF-1 and the amino-terminal and zinc finger domains of GATA-6. Whereas the zinc finger domains of GATA-4 and GATA-6 the carboxyl-terminal zinc finger domain of GATA-6 active synergistic activation of promoter in the of TTF-1. interactions between TTF-1 and GATA-6, and during morphogenesis of the lung, the concept that interactions between these members of the transcription proteins a role in the expression of target genes in the respiratory GATA-6 TTF-1 expression is to the lung during development, these transcription factors are co-expressed in peripheral respiratory epithelial cells of the lung, where they activated the expression of promoter. of are also with the expression of and surfactant including surfactant proteins and TTF-1 is expressed in the and thyroid and not with the expression of GATA-6 in these tissues J. Biol. 1997; PubMed Scopus Google Scholar). TTF-1 and GATA-6 also co-expressed in cells, with the of TTF-1 for the expression of surfactant proteins in and in to TTF-1, GATA-6 was not for activation of sp-C gene expression in HeLa the proteins synergistically activated the of the GATA-6 and TTF-1 the sp-C promoter. for the binding for GATA-6 to and to and TTF-1 to are the sp-C promoter, with the of protein to directly S.E. Bachurski C.J. Burhans M.S. Glasser S.W. J. Biol. Chem. 1996; 271: 6881-6888Abstract Full Text Full Text PDF PubMed Scopus (216) Google Scholar). of the and GATA in the sp-C promoter also and interactions between these factors in the gene expression and the expression of for the between GATA and family members R. R.J. J. 1997; PubMed Scopus Google Scholar). GATA-4 and synergistically activated gene expression in and interactions between the proteins in in assays R.J. Mol. Cell. Biol. PubMed Scopus Google Scholar). interactions between and GATA-4 also the zinc finger domain in GATA-4 and the homeodomain of the to between TTF-1 and GATA-6. and J. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, C.J. J. R. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google the role of zinc finger domain as a the zinc finger of GATA-6 both binding and with TTF-1, the of these interactions was by substitution the carboxyl-terminal zinc finger of GATA-4 for that of GATA-6 by of Whereas GATA-6 binding activity to the GATA its to the sp-C promoter in a synergistic was of of the GATA-6 with TTF-1 is by interactions between TTF-1 and the carboxyl-terminal zinc finger domain of GATA-6 by in the binding domain is both and interacted with TTF-1 in the two-hybrid the activity of GATA-6 to to TTF-1 was not directly with the to synergistically promoter, by GATA-6 influence its TTF-1 is to interact with a number of transcription factors with binding in to the TTF-1 and GATA-6 are to interact in both with and with protein in the of the target TTF-1 and with and in in the activation of the gene promoter Am. J. Mol. Biol. 2001; PubMed Scopus Google Scholar, Whitsett J.A. Yan C. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar, Wert S. Whitsett J.A. Yan C. Am. J. Physiol. 2000; PubMed Google Scholar). TTF-1 and synergistically the sp-C promoter with nuclear binding to in to both GATA-6 and TTF-1-binding GATA-6, TTF-1, and and also influence to target gene expression during lung binding and with the in surfactant protein promoter GATA-4 with TTF-1, not synergistically the sp-C promoter in HeLa cells as as GATA-6, that the binding is not for between GATA and family by GATA-6 or GATA-4 by including binding to GATA or by the formation of transcription by or interactions between TTF-1 and GATA-6 or TTF-1, GATA-6, and transcription GATA-6 and TTF-1 but in lung morphogenesis and gene expression. TTF-1 is required for the formation of the lung during lung lung peripheral lung P. Su G. Drum H. Bringas P. Kimura S. Dev. Biol. 1999; 209: 60-71Crossref PubMed Scopus (353) Google Scholar). TTF-1 is required for expression of surfactant proteins and in the respiratory in and in S.E. Bachurski C.J. Burhans M.S. Glasser S.W. J. Biol. Chem. 1996; 271: 6881-6888Abstract Full Text Full Text PDF PubMed Scopus (216) Google L. Whitsett J.A. Stripp B.R. Biochim. Biophys. Acta. 1997; 1350: 359-367Crossref PubMed Scopus (126) Google Scholar, C. Whitsett J.A. J. Biol. Chem. 1995; 270: Full Text Full Text PDF PubMed Scopus Google Scholar, C. Whitsett J.A. J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). GATA-6 gene transcription binding and the gene promoter M.D. Whitsett J.A. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). GATA-6 is required for endoderm formation and of GATA-6 was during lung formation E.E. M.S. Dev. PubMed Scopus Google R. C. 2001; PubMed Google that later in lung GATA-6 plays in the expression of surfactant protein activation of the promoter not and in the of target gene these of GATA-6 surfactant protein and gene transcription to of expression of and in the lung to TTF-1 and GATA-6 interact in of target TTF-1 and GATA-6 directly to and GATA in the surfactant protein promoter. GATA-6 and TTF-1 directly interact the zinc finger domain of GATA-6 and the homeodomain of TTF-1. TTF-1 with transcription factors, including and to influence the activity of the surfactant protein promoter. Lung structure and respiratory epithelial cell gene expression are determined by the actions of a number of nuclear transcription factors, including members of homeodomain, Forkhead, and zinc finger families of proteins (1Costa R.H. Kalinichenko V.V. Lim L. Am. J. Physiol. 2001; 280: L823-L838Crossref PubMed Google Scholar, 2Perl A.K. Whitsett J.A. Clin. Genet. 1999; 56: 14-27Crossref PubMed Scopus (124) Google Scholar). Members of these families of transcription factors are expressed in the foregut endoderm during lung morphogenesis and in subsets of respiratory epithelial cells later in development, where they influence the expression of genes selectively expressed in the lung, including surfactant proteins SP-A, -B, -C, and Clara cell secretory protein (CCSP)1(3Di Bohinski R.J. Lauro R. Whitsett J.A. Mol. Cell. Biol. 1994; 14: 5671-5681Crossref PubMed Scopus (484) Google Scholar, 4Bruno M.D. Bohinski R.J. Huelsman K.M. Whitsett J.A. Korfhagen T.R. J. Biol. Chem. 1995; 270: 6531-6536Abstract Full Text Full Text PDF PubMed Scopus (238) Google Scholar, 5Bruno M.D. Korfhagen T.R. Liu C. Morrisey E.E. Whitsett J.A. J. Biol. Chem. 2000; 275: 1043-1049Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar, 6Kelly S.E. Bachurski C.J. Burhans M.S. Glasser S.W. J. Biol. Chem. 1996; 271: 6881-6888Abstract Full Text Full Text PDF PubMed Scopus (216) Google Scholar, 7Tichelaar J.W. Lim L. Costa R.H. Whitsett J.A. Dev. Biol. 1999; 213: 405-417Crossref PubMed Scopus (63) Google Scholar, 8Zhang L. Whitsett J.A. Stripp B.R. Biochim. Biophys. Acta. 1997; 1350: 359-367Crossref PubMed Scopus (126) Google Scholar, 9Zhou L. Dey C.R. Wert S.E. Yan C. Costa R.H. Whitsett J.A. Dev. Dyn. 1997; 210: 305-314Crossref PubMed Scopus (64) Google Scholar). Thyroid transcription factor-1 (TTF-1), a member of the family of homeodomain-containing transcription factors, plays a critical role in both lung morphogenesis and in respiratory epithelial cell gene expression. TTF-1 is required for the transcription of surfactant proteins and for the formation and differentiation of epithelial cells lining the peripheral respiratory tract (3Di Bohinski R.J. Lauro R. Whitsett J.A. Mol. Cell. Biol. 1994; 14: 5671-5681Crossref PubMed Scopus (484) Google Scholar, 4Bruno M.D. Bohinski R.J. Huelsman K.M. Whitsett J.A. Korfhagen T.R. J. Biol. Chem. 1995; 270: 6531-6536Abstract Full Text Full Text PDF PubMed Scopus (238) Google Scholar, 6Kelly S.E. Bachurski C.J. Burhans M.S. Glasser S.W. J. Biol. Chem. 1996; 271: 6881-6888Abstract Full Text Full Text PDF PubMed Scopus (216) Google Scholar, 8Zhang L. Whitsett J.A. Stripp B.R. Biochim. Biophys. Acta. 1997; 1350: 359-367Crossref PubMed Scopus (126) Google Scholar, 10Minoo P. Su G. Drum H. Bringas P. Kimura S. Dev. Biol. 1999; 209: 60-71Crossref PubMed Scopus (353) Google Scholar, 11Yuan C. Kimura S. B.R. P. Dev. Dyn. 2000; PubMed Scopus Google Scholar). TTF-1, also is a member of the family of transcription factors that element the containing in of target genes G. L. S. S. S. Lauro R. 1994; PubMed Scopus Google Scholar). and in the surfactant protein and gene are required for the activity of the surfactant TTF-1 directly gene expression when expressed in epithelial is that TTF-1 with a number of transcription factors, of target TTF-1 with retinoic acid receptors and C. J. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google nuclear family members Bachurski C.J. Yan C. Whitsett J.A. Am. J. Physiol. 1999; Google and Am. J. Mol. Biol. 2001; PubMed Scopus Google Scholar). the and of target genes, TTF-1 directly or with these factors to gene expression. these interactions are by interactions the transcription factors, or in with transcription factors, is GATA-6 is a member of a family of nuclear transcription factors that to GATA containing zinc finger GATA family of proteins as and are in cell differentiation and gene and and influence endodermally and derived including lung and R. A.K. J. 1997; Full Text PDF PubMed Scopus Google Scholar, Mol. Cell. Biol. PubMed Scopus Google Scholar, S. Dev. Genet. PubMed Scopus Google Scholar, C. C. J. Biol. Chem. 1994; Full Text PDF PubMed Google Scholar, E.E. M.S. Dev. Biol. 1996; PubMed Scopus Google Scholar, 1999; Google Scholar). GATA-6 was in the and lung in the E.E. M.S. Dev. Biol. 1996; PubMed Scopus Google Scholar). GATA family members the domain and binding the of GATA family members is to by with transcription factors or to transcription of target genes R. R.J. J. 1997; PubMed Scopus Google Scholar, J. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, C.J. J. R. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, R.J. Mol. Cell. Biol. PubMed Scopus Google Scholar, J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar). in GATA-4 is co-expressed with in cells R.J. Mol. Cell. Biol. PubMed Scopus Google and is that but not GATA-6 or directly and M.D. Whitsett J.A. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google GATA-6 was to to in the of the gene expression of GATA-6 and TTF-1 in the lung and with the of expression of surfactant including L. Lim L. Costa R.H. Whitsett J.A. J. 1996; PubMed Scopus Google Scholar). S.W. Burhans M.S. Korfhagen T.R. Whitsett J.A. S. 2001; PubMed Scopus (238) Google demonstrated the critical role of surfactant in surfactant and of lung GATA-6 gene transcription in M.D. Korfhagen T.R. Liu C. Morrisey E.E. Whitsett J.A. J. Biol. Chem. 2000; 275: 1043-1049Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar). was to GATA-6 influences the activity of the surfactant promoter and GATA-6 and TTF-1 might directly interact interactions between GATA-6 and TTF-1 and synergistic the transcription of the promoter. and TTF-1 synergistically the activity of the surfactant protein promoter. of the transcription factors was by and two-hybrid binding was the homeodomain of TTF-1 and the amino-terminal and zinc finger domains of GATA-6. Whereas the zinc finger domains of GATA-4 and GATA-6 the carboxyl-terminal zinc finger domain of GATA-6 active synergistic activation of promoter in the of TTF-1. interactions between TTF-1 and GATA-6, and during morphogenesis of the lung, the concept that interactions between these members of the transcription proteins a role in the expression of target genes in the respiratory GATA-6 TTF-1 expression is to the lung during development, these transcription factors are co-expressed in peripheral respiratory epithelial cells of the lung, where they activated the expression of promoter. of are also with the expression of and surfactant including surfactant proteins and TTF-1 is expressed in the and thyroid and not with the expression of GATA-6 in these tissues J. Biol. 1997; PubMed Scopus Google Scholar). TTF-1 and GATA-6 also co-expressed in cells, with the of TTF-1 for the expression of surfactant proteins in and in to TTF-1, GATA-6 was not for activation of sp-C gene expression in HeLa the proteins synergistically activated the of the GATA-6 and TTF-1 the sp-C promoter. for the binding for GATA-6 to and to and TTF-1 to are the sp-C promoter, with the of protein to directly S.E. Bachurski C.J. Burhans M.S. Glasser S.W. J. Biol. Chem. 1996; 271: 6881-6888Abstract Full Text Full Text PDF PubMed Scopus (216) Google Scholar). of the and GATA in the sp-C promoter also and interactions between these factors in the gene expression and the expression of for the between GATA and family members R. R.J. J. 1997; PubMed Scopus Google Scholar). GATA-4 and synergistically activated gene expression in and interactions between the proteins in in assays R.J. Mol. Cell. Biol. PubMed Scopus Google Scholar). interactions between and GATA-4 also the zinc finger domain in GATA-4 and the homeodomain of the to between TTF-1 and GATA-6. and J. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, C.J. J. R. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google the role of zinc finger domain as a the zinc finger of GATA-6 both binding and with TTF-1, the of these interactions was by substitution the carboxyl-terminal zinc finger of GATA-4 for that of GATA-6 by of Whereas GATA-6 binding activity to the GATA its to the sp-C promoter in a synergistic was of of the GATA-6 with TTF-1 is by interactions between TTF-1 and the carboxyl-terminal zinc finger domain of GATA-6 by in the binding domain is both and interacted with TTF-1 in the two-hybrid the activity of GATA-6 to to TTF-1 was not directly with the to synergistically promoter, by GATA-6 influence its TTF-1 is to interact with a number of transcription factors with binding in to the TTF-1 and GATA-6 are to interact in both with and with protein in the of the target TTF-1 and with and in in the activation of the gene promoter Am. J. Mol. Biol. 2001; PubMed Scopus Google Scholar, Whitsett J.A. Yan C. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar, Wert S. Whitsett J.A. Yan C. Am. J. Physiol. 2000; PubMed Google Scholar). TTF-1 and synergistically the sp-C promoter with nuclear binding to in to both GATA-6 and TTF-1-binding GATA-6, TTF-1, and and also influence to target gene expression during lung binding and with the in surfactant protein promoter GATA-4 with TTF-1, not synergistically the sp-C promoter in HeLa cells as as GATA-6, that the binding is not for between GATA and family by GATA-6 or GATA-4 by including binding to GATA or by the formation of transcription by or interactions between TTF-1 and GATA-6 or TTF-1, GATA-6, and transcription GATA-6 and TTF-1 but in lung morphogenesis and gene expression. TTF-1 is required for the formation of the lung during lung lung peripheral lung P. Su G. Drum H. Bringas P. Kimura S. Dev. Biol. 1999; 209: 60-71Crossref PubMed Scopus (353) Google Scholar). TTF-1 is required for expression of surfactant proteins and in the respiratory in and in S.E. Bachurski C.J. Burhans M.S. Glasser S.W. J. Biol. Chem. 1996; 271: 6881-6888Abstract Full Text Full Text PDF PubMed Scopus (216) Google L. Whitsett J.A. Stripp B.R. Biochim. Biophys. Acta. 1997; 1350: 359-367Crossref PubMed Scopus (126) Google Scholar, C. Whitsett J.A. J. Biol. Chem. 1995; 270: Full Text Full Text PDF PubMed Scopus Google Scholar, C. Whitsett J.A. J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). GATA-6 gene transcription binding and the gene promoter M.D. Whitsett J.A. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). GATA-6 is required for endoderm formation and of GATA-6 was during lung formation E.E. M.S. Dev. PubMed Scopus Google R. C. 2001; PubMed Google that later in lung GATA-6 plays in the expression of surfactant protein activation of the promoter not and in the of target gene these of GATA-6 surfactant protein and gene transcription to of expression of and in the lung to TTF-1 and GATA-6 interact in of target TTF-1 and GATA-6 directly to and GATA in the surfactant protein promoter. GATA-6 and TTF-1 directly interact the zinc finger domain of GATA-6 and the homeodomain of TTF-1. TTF-1 with transcription factors, including and to influence the activity of the surfactant protein promoter. GATA-6 and TTF-1 synergistically the activity of the surfactant protein promoter. of the transcription factors was by and two-hybrid binding was the homeodomain of TTF-1 and the amino-terminal and zinc finger domains of GATA-6. Whereas the zinc finger domains of GATA-4 and GATA-6 the carboxyl-terminal zinc finger domain of GATA-6 active synergistic activation of promoter in the of TTF-1. interactions between TTF-1 and GATA-6, and during morphogenesis of the lung, the concept that interactions between these members of the transcription proteins a role in the expression of target genes in the respiratory Whereas GATA-6 TTF-1 expression is to the lung during development, these transcription factors are co-expressed in peripheral respiratory epithelial cells of the lung, where they activated the expression of promoter. of are also with the expression of and surfactant including surfactant proteins and TTF-1 is expressed in the and thyroid and not with the expression of GATA-6 in these tissues J. Biol. 1997; PubMed Scopus Google Scholar). TTF-1 and GATA-6 also co-expressed in cells, with the of TTF-1 for the expression of surfactant proteins in and in to TTF-1, GATA-6 was not for activation of sp-C gene expression in HeLa the proteins synergistically activated the of the GATA-6 and TTF-1 the sp-C promoter. for the binding for GATA-6 to and to and TTF-1 to are the sp-C promoter, with the of protein to directly S.E. Bachurski C.J. Burhans M.S. Glasser S.W. J. Biol. Chem. 1996; 271: 6881-6888Abstract Full Text Full Text PDF PubMed Scopus (216) Google Scholar). of the and GATA in the sp-C promoter also and interactions between these factors promoter. in the gene expression and the expression of for the between GATA and family members R. R.J. J. 1997; PubMed Scopus Google Scholar). GATA-4 and synergistically activated gene expression in and interactions between the proteins in in assays R.J. Mol. Cell. Biol. PubMed Scopus Google Scholar). interactions between and GATA-4 also the zinc finger domain in GATA-4 and the homeodomain of the to between TTF-1 and GATA-6. and J. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, C.J. J. R. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google the role of zinc finger domain as a the zinc finger of GATA-6 both binding and with TTF-1, the of these interactions was by substitution the carboxyl-terminal zinc finger of GATA-4 for that of GATA-6 by of Whereas GATA-6 binding activity to the GATA its to the sp-C promoter in a synergistic was of of the GATA-6 with TTF-1 is by interactions between TTF-1 and the carboxyl-terminal zinc finger domain of GATA-6 by in the binding domain is both and interacted with TTF-1 in the two-hybrid the activity of GATA-6 to to TTF-1 was not directly with the to synergistically promoter, by GATA-6 influence its TTF-1 is to interact with a number of transcription factors with binding in to the TTF-1 and GATA-6 are to interact in both with and with protein in the of the target TTF-1 and with and in in the activation of the gene promoter Am. J. Mol. Biol. 2001; PubMed Scopus Google Scholar, Whitsett J.A. Yan C. J. Biol. 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C. 2001; PubMed Google that later in lung GATA-6 plays in the expression of surfactant protein activation of the promoter not and in the of target gene these of GATA-6 surfactant protein and gene transcription to of expression of and in the lung to TTF-1 and GATA-6 interact in of target TTF-1 and GATA-6 directly to and GATA in the surfactant protein promoter. GATA-6 and TTF-1 directly interact the zinc finger domain of GATA-6 and the homeodomain of TTF-1. TTF-1 with transcription factors, including and to influence the activity of the surfactant protein promoter. the of Wert in in Yan in two-hybrid in and in