p300 Protein as a Coactivator of GATA-5 in the Transcription of Cardiac-restricted Atrial Natriuretic Factor Gene

A cellular target of adenovirus E1A oncoprotein, p300 is a transcriptional coactivator and a negative regulator of cellular proliferation. A previous study suggests that the p300 family is also involved in cell type-specific transcription in cardiac myocytes. However, nothing is known about which cardiac transcription factor(s) interact with and transactivate through these proteins. The transcription factors GATA-4/5/6 have been implicated as key regulators of cardiogenesis, and they participate in the transcription of many cardiac-specific genes. Here we show that E1A represses the GATA-5-dependent transactivation of a promoter derived from the cardiac-restricted atrial natriuretic factor gene. This repression is correlated with the interaction of E1A with p300, indicating that p300 participates in GATA-5-dependent transactivation. E1A markedly down-regulates endogenous atrial natriuretic factor expression, as well as disrupts the interaction between p300 and GATA-5. A small fragment of p300 containing the carboxyl-terminal cysteine/histidine-rich domain, sufficient to interact with GATA-5, prevents transcriptional activation by GATA-5 as a dominant-negative mutant. Consistent with its role as a coactivator, p300 markedly potentiates GATA-5-activated transcription. These results implicate p300 as an important component of myocardial cell differentiation and provide an insight into the relationship between mechanisms that mediate cell type-specific transcription and cell cycle regulation during cardiogenesis. A cellular target of adenovirus E1A oncoprotein, p300 is a transcriptional coactivator and a negative regulator of cellular proliferation. A previous study suggests that the p300 family is also involved in cell type-specific transcription in cardiac myocytes. However, nothing is known about which cardiac transcription factor(s) interact with and transactivate through these proteins. The transcription factors GATA-4/5/6 have been implicated as key regulators of cardiogenesis, and they participate in the transcription of many cardiac-specific genes. Here we show that E1A represses the GATA-5-dependent transactivation of a promoter derived from the cardiac-restricted atrial natriuretic factor gene. This repression is correlated with the interaction of E1A with p300, indicating that p300 participates in GATA-5-dependent transactivation. E1A markedly down-regulates endogenous atrial natriuretic factor expression, as well as disrupts the interaction between p300 and GATA-5. A small fragment of p300 containing the carboxyl-terminal cysteine/histidine-rich domain, sufficient to interact with GATA-5, prevents transcriptional activation by GATA-5 as a dominant-negative mutant. Consistent with its role as a coactivator, p300 markedly potentiates GATA-5-activated transcription. These results implicate p300 as an important component of myocardial cell differentiation and provide an insight into the relationship between mechanisms that mediate cell type-specific transcription and cell cycle regulation during cardiogenesis. retinoblastoma atrial natriuretic factor base pair(s) chloramphenicol acetyltransferase cAMP-response element binding protein binding protein cytomegalovirus electrophoretic mobility shift assay β-galactosidase glyceraldehyde-3-phosphate dehydrogenase luciferase wild type mutant deletion Rous sarcoma virus Cardiac myocytes are highly differentiated cells, the structural and functional properties of which are especially suited to maintain normal blood flow. The differentiated status of these cells is maintained by the expression of muscle-specific genes, the formation of sarcomeres, and rhythmic contractions (reviewed in Ref. 1Litvin J. Montgomery M. Gonzalez-Sanchez A. Bisaha J.G. Bader D. Trends Cardiovasc. Med. 1992; 2: 27-32Crossref PubMed Scopus (41) Google Scholar). In contrast to skeletal myogenesis, a subset of differentiated cardiac myocytes continues to undergo cell division (2Goldstein M.A. Claycomb W.C. Schwartz A. Science. 1974; 183: 212-213Crossref PubMed Scopus (28) Google Scholar). However, during late gestation, increasing proportions of these cells arrest irreversibly in the G1 phase of the cell cycle (3Claycomb W.C. J. Biol. Chem. 1975; 250: 3229-3335Abstract Full Text PDF PubMed Google Scholar, 4Rumyantsev P.P. Int. Rev. Cytol. 1977; 51: 187-273Crossref Scopus (273) Google Scholar). Therefore, adult cardiac myocytes no longer have the ability to proliferate, and further growth is limited to hypertrophy, i.e. an increase in cell volume but not in number. As such, the identification of the signaling pathways that mediate cardiac myocyte differentiation is critical to the ultimate elucidation of the molecular basis of cardiac muscle hypertrophy and failure. Clues regarding cellular proteins that regulate aspects of cardiac muscle differentiation have been provided by the effects of the adenovirus E1A oncoprotein in these cells. When E1A is expressed in already differentiated cardiac muscle cells, it stimulates cellular DNA synthesis and represses muscle-specific gene expression (5Kirshenbaum L.A. Schneider M.D. J. Biol. Chem. 1995; 270: 7791-7794Abstract Full Text Full Text PDF PubMed Scopus (139) Google Scholar, 6Liu Y. Kitsis R.N. J. Cell Biol. 1996; 133: 325-334Crossref PubMed Scopus (78) Google Scholar, 7Hasegawa K. Meyers M.B. Kitsis R.N. J Biol Chem. 1997; 272: 20049-20054Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar). E1A interacts with at least two classes of cellular factors, namely, the p300 and Rb1 families (reviewed in Ref. 8Moran E. Curr. Opin. Genet. Dev. 1993; 3: 63-70Crossref PubMed Scopus (234) Google Scholar). As for the Rb pathway, adenovirus E1A targets the “pocket” domain of Rb and its relatives p107 and p130/Rb2, thereby perturbing normal cellular interaction with the transcription factor E2F/DP. Nevertheless, studies with E1A mutants indicate that interference with the p300 pathway is sufficient to stimulate DNA synthesis and repress muscle-specific gene expression in cardiac myocytes (5Kirshenbaum L.A. Schneider M.D. J. Biol. Chem. 1995; 270: 7791-7794Abstract Full Text Full Text PDF PubMed Scopus (139) Google Scholar, 6Liu Y. Kitsis R.N. J. Cell Biol. 1996; 133: 325-334Crossref PubMed Scopus (78) Google Scholar, 7Hasegawa K. Meyers M.B. Kitsis R.N. J Biol Chem. 1997; 272: 20049-20054Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar). These experiments suggest that p300 proteins are involved in maintaining both cell type-specific gene expression and cell cycle arrest in cardiac myocytes. p300 proteins are classified as the transcriptional coactivator that communicates between transactivators binding on enhancer DNA and the basal transcriptional complex formed on the promoter near the transcription initiation site (9Eckner R. Ewen M.E. Newsome D. Gerdes M. Decaprio J.A. Lawrence J.B. Livingston D.M. Genes Dev. 1994; 8: 869-884Crossref PubMed Scopus (927) Google Scholar). This communication is required for transcriptional activation by the transactivators. Consistent with this view, the p300 family of transcriptional coactivators has been noted to modulate many examples of enhancer-mediated transcription (9Eckner R. Ewen M.E. Newsome D. Gerdes M. Decaprio J.A. Lawrence J.B. Livingston D.M. Genes Dev. 1994; 8: 869-884Crossref PubMed Scopus (927) Google Scholar, 10Chrivia J.C. Kwok R.P. Lamb N. Hagiwara M. Montiminy M.R. Goodman R.H. Nature. 1993; 365: 855-859Crossref PubMed Scopus (1770) Google Scholar, 11Kwok R.P.S. Lundblad J.R. Chrivia J.C. Richards J.P. Bachinger H.P. Brennan R.G. Roberts S.G.E. Green M.R. Goodman R.H. Nature. 1994; 370: 223-226Crossref PubMed Scopus (1283) Google Scholar, 12Arias J. Alberts A.S. Brindle P. Claret F.X. Smeal T. Karin M. Feramisco J. Montiminy M. Nature. 1994; 370: 226-229Crossref PubMed Scopus (681) Google Scholar, 13Arany Z. Newsome D. Oldread E. Livingston D.M. Eckner R. Nature. 1995; 374: 81-84Crossref PubMed Scopus (492) Google Scholar, 14Lundblad J.R. Kwok R.P. Laurence M.E. Harter M.L. Goodman R.H. Nature. 1995; 374: 85-88Crossref PubMed Scopus (531) Google Scholar, 15Lee J.S. Galvin K.M. See R.H. Eckner R. Livingston D. Moran E. Shi Y. Genes Dev. 1995; 9: 1188-1198Crossref PubMed Scopus (281) Google Scholar, 16Missero C. Calautti E. Eckner R. Chin J. Tsai L.H. Livingston D.M. Dotto G.P. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 5451-5455Crossref PubMed Scopus (329) Google Scholar, 17Bannister A.J. Kouzarides T. EMBO. J. 1995; 14: 4758-4762Crossref PubMed Scopus (319) Google Scholar, 18Yuan W. Condorelli G. Caruso M. Felsani A. Giordano A. J. Biol. Chem. 1996; 271: 9009-9013Abstract Full Text Full Text PDF PubMed Scopus (277) Google Scholar, 19Eckner R. Yao T.-P. Oldread E. Livingston D.M. Genes Dev. 1996; 10: 2478-2490Crossref PubMed Scopus (320) Google Scholar, 20Sartorelli V. Huang J. Hamamori Y. Kedes L. Mol. Biol. 1997; PubMed Scopus Google Scholar, M.L. C. N. A. Giordano A. J. 1997; PubMed Scopus Google Scholar, Y. L. T. J. R. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar, D. T. M.R. Nature. 1996; PubMed Scopus Google Scholar, P. Y. T. C. T. S. Genes Dev. 1996; 10: PubMed Scopus Google Scholar, M. R. J. S. J. 1996; PubMed Scopus Google Scholar, D. Kouzarides T. Proc. Natl. Acad. Sci. U. S. A. 1996; PubMed Scopus Google Scholar, R. A. 1996; Google Scholar). The of this p300 and the cAMP-response element binding protein binding protein interact with of the basal transcriptional and protein R.P.S. Lundblad J.R. Chrivia J.C. Richards J.P. Bachinger H.P. Brennan R.G. Roberts S.G.E. Green M.R. Goodman R.H. Nature. 1994; 370: 223-226Crossref PubMed Scopus (1283) Google Scholar, 18Yuan W. Condorelli G. Caruso M. Felsani A. Giordano A. J. Biol. Chem. 1996; 271: 9009-9013Abstract Full Text Full Text PDF PubMed Scopus (277) Google Scholar, S. P. Moran E. 1993; 8: Google and proteins. A p300 protein a complex with a by which p300 the in the G1 phase of the cell cycle D. J. Livingston D.M. Nature. 1997; PubMed Scopus Google M.L. V. K. Giordano A. A.S. K. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). In skeletal are transcriptional for and and these are required for W. Condorelli G. Caruso M. Felsani A. Giordano A. J. Biol. Chem. 1996; 271: 9009-9013Abstract Full Text Full Text PDF PubMed Scopus (277) Google Scholar, 19Eckner R. Yao T.-P. Oldread E. Livingston D.M. Genes Dev. 1996; 10: 2478-2490Crossref PubMed Scopus (320) Google Scholar, 20Sartorelli V. Huang J. Hamamori Y. Kedes L. Mol. Biol. 1997; PubMed Scopus Google Scholar, M.L. C. N. A. Giordano A. J. 1997; PubMed Scopus Google Scholar). In to p300 proteins V. Y. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar, A.J. Kouzarides T. Nature. 1996; PubMed Scopus Google which is to a and the role by p300 in cardiac-specific transcription as the as to which transcription factor(s) interact with and transactivate through these proteins in cardiac myocytes. E1A repress the transcription of many cardiac (5Kirshenbaum L.A. Schneider M.D. J. Biol. Chem. 1995; 270: 7791-7794Abstract Full Text Full Text PDF PubMed Scopus (139) Google Scholar, 6Liu Y. Kitsis R.N. J. Cell Biol. 1996; 133: 325-334Crossref PubMed Scopus (78) Google Scholar, 7Hasegawa K. Meyers M.B. Kitsis R.N. J Biol Chem. 1997; 272: 20049-20054Abstract Full Text Full Text PDF PubMed Scopus (46) Google p300 interact with key regulators expressed in these cells. The suggests the of a of transcription factors, in cardiogenesis. the expression of GATA-4/5/6 is to the and Mol. Biol. 1993; PubMed Google Scholar, C. L. L. L. T. M. Mol. Biol. 1994; 14: PubMed Scopus Google Scholar, C. T. 1993; PubMed Google Scholar, C. C. J.B. T. J. Biol. Chem. 1994; Full Text PDF PubMed Google Scholar, T. Dev. Biol. 1996; PubMed Scopus Google Scholar). are at of and cardiac C. T. 1993; PubMed Google Scholar, C. C. J.B. T. J. Biol. Chem. 1994; Full Text PDF PubMed Google Scholar, T. Dev. Biol. 1996; PubMed Scopus Google Scholar, M. Dev. Biol. 1994; PubMed Scopus Google Scholar, Biol. 1996; PubMed Scopus Google Scholar, Dev. Biol. 1997; 183: PubMed Scopus Google Scholar). this of factors the many cardiac-specific they as regulators C. L. L. L. T. M. Mol. Biol. 1994; 14: PubMed Scopus Google Scholar, M. Z. Mol. Biol. 1994; 14: PubMed Scopus Google Scholar, Mol. Biol. 1994; 14: PubMed Google Scholar). that to a of the two and R. K. C. Genes Dev. 1997; 10: Scholar, Genes Dev. 1997; PubMed Scopus Google Scholar). these critical of factors in cardiogenesis, the expression of is not sufficient to cardiac that are required T. Dev. Biol. 1996; PubMed Scopus Google Scholar, C. L. T. M. Mol. Biol. 1995; PubMed Scopus Google C. G. M. 1997; PubMed Google Scholar). These to p300 and GATA-4/5/6 interact with and regulate a subset of cardiac muscle-specific genes. As a cardiac-specific we a promoter derived from the atrial natriuretic factor which is expressed in at the cells are to the cardiac and expression both atrial and but not skeletal muscle cells, that the gene a to cardiac that p300 and GATA-5 in the cardiac-restricted promoter and that these proteins interact in This molecular interaction further into the relationship between mechanisms that mediate cell type-specific transcription and cell cycle regulation during cardiogenesis. The and of the luciferase by of of promoter K. Meyers M.B. Kitsis R.N. J Biol Chem. 1997; 272: 20049-20054Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar). of the element in the promoter by a of promoter with type promoter with also by and the chloramphenicol acetyltransferase and the gene by Rous sarcoma virus K. Meyers M.B. Kitsis R.N. J Biol Chem. 1997; 272: 20049-20054Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar, K. Kitsis R.N. 1997; PubMed Scopus Google Scholar). The GATA-5 and expression Dev. Biol. 1997; 183: PubMed Scopus Google and Biol. 1996; PubMed Scopus Google from S. of and are The expression by Mol. Biol. 1993; PubMed Google Scholar, M. Z. Mol. Biol. 1994; 14: PubMed Scopus Google by with to a and by the fragment the into the site of the expression is a expression for wild type is derived from an deletion of E1A between and Z. Newsome D. Oldread E. Livingston D.M. Eckner R. Nature. 1995; 374: 81-84Crossref PubMed Scopus (492) Google Scholar). and the cytomegalovirus to β-galactosidase a p300 (9Eckner R. Ewen M.E. Newsome D. Gerdes M. Decaprio J.A. Lawrence J.B. Livingston D.M. Genes Dev. 1994; 8: 869-884Crossref PubMed Scopus (927) Google p300 with an deletion in the E1A binding domain (9Eckner R. Ewen M.E. Newsome D. Gerdes M. Decaprio J.A. Lawrence J.B. Livingston D.M. Genes Dev. 1994; 8: 869-884Crossref PubMed Scopus (927) Google a of p300 W. Condorelli G. Caruso M. Felsani A. Giordano A. J. Biol. Chem. 1996; 271: 9009-9013Abstract Full Text Full Text PDF PubMed Scopus (277) Google and from Eckner and M. Livingston and provided by Giordano by by the and on with to cells cells maintained in with The cells with and with a of of DNA in to the a with the cells with and further in the with for The cells with and as K. Meyers M.B. Kitsis R.N. J Biol Chem. 1997; 272: 20049-20054Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar, K. Kitsis R.N. 1997; PubMed Scopus Google Scholar). and in the cell as K. Meyers M.B. Kitsis R.N. J Biol Chem. 1997; 272: 20049-20054Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar, K. Kitsis R.N. 1997; PubMed Scopus Google Scholar). The from the of and expressed as the the and A from cells with that from the The of the of these as C. L. T. M. Mol. Biol. 1995; PubMed Scopus Google element in the M. Z. Mol. Biol. 1994; 14: PubMed Scopus Google by and by as K. Kitsis R.N. 1997; PubMed Scopus Google at for in containing of of of and a of in the binding by on in and at for from from cells with of and of of the an GATA-5 normal in and and for at and with protein for at The in the in of to for by an to an and with p300 of and which the to the cardiac myocytes from of as K. Meyers M.B. Kitsis R.N. J Biol Chem. 1997; 272: 20049-20054Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar). cells with and with of to the a with the cells with and further for of of from these cells as K. Meyers M.B. Kitsis R.N. J Biol Chem. 1997; 272: 20049-20054Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar, K. Kitsis R.N. 1997; PubMed Scopus Google Scholar). A of the fragment of K. Kitsis R.N. 1997; PubMed Scopus Google which by and to as K. Meyers M.B. Kitsis R.N. J Biol Chem. 1997; 272: 20049-20054Abstract Full Text Full Text PDF PubMed Scopus (46) Google K. Kitsis R.N. 1997; PubMed Scopus Google Scholar). of by of to of of the transcription factor and are expressed in the Mol. Biol. 1993; PubMed Google Scholar, C. L. L. L. T. M. Mol. Biol. 1994; 14: PubMed Scopus Google Scholar, C. T. 1993; PubMed Google Scholar, C. C. J.B. T. J. Biol. Chem. 1994; Full Text PDF PubMed Google Scholar, T. Dev. Biol. 1996; PubMed Scopus Google Scholar). The of the promoter two and C. L. L. L. T. M. Mol. Biol. 1994; 14: PubMed Scopus Google Scholar). a expression of GATA-4/5/6 transactivate the cardiac-restricted promoter the in cells, we experiments cells, which not a expression by the promoter with a expression of GATA-4/5/6 β-galactosidase as a The by As in the expression of GATA-5 in a activation of the the expression of in activation and In of GATA-4/5/6 a promoter experiments the promoter containing the site which the binding of GATA-5 as that the transactivation of the promoter by and but not These that GATA-5 to a transactivate the cardiac-restricted promoter through the of between the site and GATA-5. studies in from cells GATA-5 β-galactosidase with a containing the at a as wild type GATA-5 binding site in the cardiac with a that the transcription and The the complex to the interaction between the site and studies the in from cells GATA-5 in the of of the of as are The the complex to the interaction between the site and GATA-5, and the of the GATA-5-dependent the in the promoter interact with GATA-5, from cells GATA-5 with a containing the site in the of that a binding as by the that it by a of The in from cells as a The also by an that the in the cardiac promoter C. C. M.B. J. 1993; PubMed Google to a binding site of GATA-5. In contrast to the wild type the shift not by an of an containing the at which been to GATA-5 by the of a the of the further that the an interaction of the with GATA-5, we As in the which by an of by but not by GATA-5 the site in a the that p300 is involved in GATA-5-activated transcription in cells, we an with an expression wild type E1A an E1A mutant an deletion that its ability to to p300, but not to Rb family proteins C. C. M.B. J. 1993; PubMed Google Scholar, A. C. P. Google Scholar, N. A. Giordano A. Mol. Cell 1995; 3: Scholar). the GATA-5-dependent promoter When we it the with the wild type indicating that the repression by E1A its binding to a between the repression by E1A of GATA-5-dependent transcription and the binding of E1A to p300 we the of the of p300 on this transcriptional p300 in the we p300 a p300 mutant that required for E1A binding and by E1A (9Eckner R. Ewen M.E. Newsome D. Gerdes M. Decaprio J.A. Lawrence J.B. Livingston D.M. Genes Dev. 1994; 8: 869-884Crossref PubMed Scopus (927) Google Scholar). The of the repression by E1A of GATA-5-dependent promoter In the of no on the repression of p300 the repression by E1A of GATA-5-dependent and this is of E1A These results suggest that the binding by E1A of a p300 family is to its transcriptional repression of the promoter indicating that p300 is involved in GATA-5-dependent transactivation. on the coactivator role of p300, its in GATA-5-dependent transactivation that p300 interact with GATA-5. this we by cells with an expression GATA-5 that p300 both and derived from the cells to with an as a as a negative an the that the but not p300 The not p300 protein from GATA-5 p300 p300 with GATA-5. functional studies that E1A the GATA-5-dependent promoter we the interaction of p300 with GATA-5 is correlated with these functional cells with an expression β-galactosidase E1A in to the for p300 and GATA-5. from these cells to with an and and an and by the β-galactosidase not the interaction of p300 with GATA-5 E1A this interaction the of E1A in the of differentiated cardiac we the effects of wild type and a mutant of E1A on the expression of the endogenous gene in cardiac myocytes from As in wild type and mutant E1A and expressed in cardiac myocytes with a expression no E1A expression in cardiac myocytes with a β-galactosidase expression As in the expression of the cardiac-specific gene markedly in these cells with an E1A expression with that in cells with a β-galactosidase expression However, with a mutant for p300 binding the expression of the gene. of to are in C. E1A markedly down-regulates the expression of the endogenous gene in differentiated cardiac a mutant E1A for p300 binding These suggest that endogenous p300 in these cells a role in the of gene transcription. in p300 are well many and as binding for transcription a containing the carboxyl-terminal is sufficient to mediate binding GATA-5, cells with and derived from the cells to with an of these the of a of with GATA-5 These suggest that domain of p300 is sufficient to interact with GATA-5. A small fragment of p300 the transactivation ability by W. Condorelli G. Caruso M. Felsani A. Giordano A. J. Biol. Chem. 1996; 271: 9009-9013Abstract Full Text Full Text PDF PubMed Scopus (277) Google but the ability to interact with GATA-5. These suggest that this fragment the ability of endogenous p300 to with GATA-5, thereby the GATA-5-dependent transcription. this we an into cells with GATA-5 expression in with a we the The of the a of as A of the GATA-5-dependent by the of and These results suggest that the of endogenous p300 as a dominant-negative mutant in GATA-5-dependent transcription. The of p300 in GATA-5-activated transcription and its ability to to GATA-5 suggest that p300 mediate GATA-5-dependent transactivation this we in cells. the with GATA-5 expression in with a we the In contrast to the cell the of the a of transcription in cells This by the that these cells which disrupts the of endogenous The of p300 and GATA-5 a of the the with GATA-5 Therefore, the transcriptional of GATA-5 is markedly by Cell type-specific gene expression is through the of and expressed transcription The of a element the of these factors into that the transcriptional GATA-5 to the increasing of factors of which the is by the expressed transcriptional coactivator that p300 markedly the GATA-5-dependent transcription of the The of wild type E1A a mutant E1A to p300 not repress GATA-5 is of the of cells Dev. Biol. 1997; 183: PubMed Scopus Google and critical in cardiogenesis, GATA-5 is to an important target of p300 in cardiac myocytes. proteins have been that and the C. C. J.B. T. J. Biol. Chem. 1994; Full Text PDF PubMed Google Scholar, Biol. 1996; PubMed Scopus Google Scholar, Dev. Biol. 1997; 183: PubMed Scopus Google Scholar). These proteins into two containing and and with and The are by both and expression with and in blood and and and in and the and are expressed in the and the GATA-5 gene is expressed in a and the Biol. 1996; PubMed Scopus Google Scholar, Dev. Biol. 1997; 183: PubMed Scopus Google Scholar). The that GATA-5 has transactivation ability for the has activation that p300 with not GATA-5 but also and not These results are with a that in the cell with through its T. Eckner R. M. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google which is and mechanisms for the in the transactivation GATA-4/5/6 further The expression of E1A GATA-5-dependent that of a mutant E1A that p300 binding but the to interact with proteins a on transcriptional The from these is in which E1A p300 a it to participate in the transactivation. we the that E1A GATA-5 through a binding site to that for p300, of p300 in the transcription is by the that a mutant required for binding by but not wild type p300 the repression of the GATA-5-dependent transcription by In the of GATA-5-dependent transactivation by p300 that p300 participates in transactivation by the interaction between GATA-5 and the p300 is in containing and the interaction between p300 and GATA-5 proteins suggests that p300 as a between GATA-5 and the basal transcriptional complex during transactivation. This of p300 it as a transcriptional coactivator for GATA-5. The study also that a small fragment of p300 containing the carboxyl-terminal cysteine/histidine-rich domain endogenous p300 in the GATA-5-dependent transactivation of the this fragment is to GATA-5 but has no transcriptional its negative role with GATA-5 from the wild type p300 in cells dominant-negative these results the that p300 as a coactivator for GATA-5. of indicate that p300 and are required for the of the G1 phase of the cell cycle in differentiated cardiac myocytes. The binding of by E1A stimulates cardiac myocytes to undergo DNA synthesis (5Kirshenbaum L.A. Schneider M.D. J. Biol. Chem. 1995; 270: 7791-7794Abstract Full Text Full Text PDF PubMed Scopus (139) Google Scholar, 6Liu Y. Kitsis R.N. J. Cell Biol. 1996; 133: 325-334Crossref PubMed Scopus (78) Google Scholar). In with this view, p300 as coactivators of in the of cell cycle These of are by E1A D. J. Livingston D.M. Nature. 1997; PubMed Scopus Google Scholar, M.L. V. K. Giordano A. A.S. K. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). The interaction of p300 with both and cardiac-restricted factors suggest that the p300 family of transcriptional coactivators a between cell cycle arrest and cell type-specific transcription during cardiogenesis. However, differentiation and in the cardiac myocyte are not a subset of differentiated cardiac myocytes undergo cell increasing proportions of these cells arrest in G1 during late (2Goldstein M.A. Claycomb W.C. Schwartz A. Science. 1974; 183: 212-213Crossref PubMed Scopus (28) Google Scholar, W.C. J. Biol. Chem. 1975; 250: 3229-3335Abstract Full Text PDF PubMed Google Scholar, 4Rumyantsev P.P. Int. Rev. Cytol. 1977; 51: 187-273Crossref Scopus (273) Google Scholar). this we that p300 in cardiac myocytes interacts with GATA-4/5/6 at during cardiogenesis. studies are on the interaction of p300 with these proteins in a functional p300 gene T. M. N. L. D. E. Livingston D. M. Eckner R. Full Text Full Text PDF PubMed Scopus Google Scholar). for p300 between and of gestation, in The in the of cardiac muscle differentiation and in The expression of the myocardial proteins in the mutant with the wild type of These are that p300 is required for GATA-4/5/6 have been implicated in the transcription of many cardiac muscle structural proteins Biol. 1996; PubMed Scopus Google Scholar, Dev. Biol. 1997; 183: PubMed Scopus Google Scholar, M. Z. Mol. Biol. 1994; 14: PubMed Scopus Google Scholar, Mol. Biol. 1994; 14: PubMed Google Scholar). In it has been that which important in cardiac and skeletal muscle also interact with p300 V. Huang J. Hamamori Y. Kedes L. Mol. Biol. 1997; PubMed Scopus Google Scholar). proteins that are involved in cardiogenesis. of these factors in the of p300 the in the expression of myocardial proteins in the In to the critical of GATA-4/5/6 in cardiogenesis, have that cardiac factors are involved in the expression of cardiac during myocardial cell hypertrophy K. Kitsis R.N. 1997; PubMed Scopus Google Scholar, S. Proc. Natl. Acad. Sci. U. S. A. 1997; PubMed Scopus Google Scholar). is in the in limited Y. L. T. J. R. 1996; Full Text Full Text PDF PubMed Scopus Google and well to in the transcription of in to from the Therefore, it to the interaction of p300 with GATA-4/5/6 in to in cardiac myocytes.