{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T01:04:11Z","timestamp":1790816651297,"version":"4.1.0"},"reference-count":25,"publisher":"National Academy of Sciences","issue":"30","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2011,7,26]]},"abstract":"<jats:p>\n                    Cardiac hypertrophy is an adaptive growth process that occurs in response to stress stimulation or injury wherein multiple signal transduction pathways are induced, culminating in transcription factor activation and the reprogramming of gene expression. GATA4 is a critical transcription factor in the heart that is known to induce\/regulate the hypertrophic program, in part, by receiving signals from MAPKs. Here we generated knock-in mice in which a known MAPK phosphorylation site at serine 105 (S105) in\n                    <jats:italic>Gata4<\/jats:italic>\n                    that augments activity was mutated to alanine. Homozygous\n                    <jats:italic>Gata4<\/jats:italic>\n                    -\n                    <jats:italic>S105A<\/jats:italic>\n                    mutant mice were viable as adults, although they showed a compromised stress response of the myocardium. For example, cardiac hypertrophy in response to phenylephrine agonist infusion for 2 wk was largely blunted in\n                    <jats:italic>Gata4<\/jats:italic>\n                    -\n                    <jats:italic>S105A<\/jats:italic>\n                    mice, as was the hypertrophic response to pressure overload at 1 and 2 wk of applied stimulation.\n                    <jats:italic>Gata4<\/jats:italic>\n                    -\n                    <jats:italic>S105A<\/jats:italic>\n                    mice were also more susceptible to heart failure and cardiac dilation after 2 wk of pressure overload. With respect to the upstream pathway, hearts from\n                    <jats:italic>Gata4<\/jats:italic>\n                    -\n                    <jats:italic>S105A<\/jats:italic>\n                    mice did not efficiently hypertrophy following direct ERK1\/2 activation using an activated MEK1 transgene in vivo. Mechanistically, GATA4 mutant protein from these hearts failed to show enhanced DNA binding in response to hypertrophic stimulation. Moreover, hearts from\n                    <jats:italic>Gata4<\/jats:italic>\n                    -\n                    <jats:italic>S105A<\/jats:italic>\n                    mice had significant changes in the expression of hypertrophy-inducible, fetal, and remodeling-related genes.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1104499108","type":"journal-article","created":{"date-parts":[[2011,7,12]],"date-time":"2011-07-12T02:10:10Z","timestamp":1310436610000},"page":"12331-12336","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":93,"title":["Serine 105 phosphorylation of transcription factor GATA4 is necessary for stress-induced cardiac hypertrophy in vivo"],"prefix":"10.1073","volume":"108","author":[{"given":"Jop H.","family":"van Berlo","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Cincinnati Children\u2019s Hospital Medical Center, University of Cincinnati, Cincinnati, OH 45229;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John W.","family":"Elrod","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Cincinnati Children\u2019s Hospital Medical Center, University of Cincinnati, Cincinnati, OH 45229;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce J.","family":"Aronow","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Cincinnati Children\u2019s Hospital Medical Center, University of Cincinnati, Cincinnati, OH 45229;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William T.","family":"Pu","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Children\u2019s Hospital Boston, Boston, MA 02115;"},{"name":"Department of Genetics, Harvard Medical School, Boston, MA 02115; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffery D.","family":"Molkentin","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Cincinnati Children\u2019s Hospital Medical Center, University of Cincinnati, Cincinnati, OH 45229;"},{"name":"Howard Hughes Medical Institute, Cincinnati, OH 45229"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2011,7,11]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1038\/nrm1983","article-title":"Regulation of cardiac hypertrophy by intracellular signalling pathways","volume":"7","author":"Heineke J","year":"2006","unstructured":"J Heineke, JD Molkentin, Regulation of cardiac hypertrophy by intracellular signalling pathways. Nat Rev Mol Cell Biol 7, 589\u2013600 (2006).","journal-title":"Nat Rev Mol Cell Biol"},{"key":"e_1_3_4_2_2","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/j.semcdb.2006.11.012","article-title":"Re-employment of developmental transcription factors in adult heart disease","volume":"18","author":"Oka T","year":"2007","unstructured":"T Oka, J Xu, JD Molkentin, Re-employment of developmental transcription factors in adult heart disease. Semin Cell Dev Biol 18, 117\u2013131 (2007).","journal-title":"Semin Cell Dev Biol"},{"key":"e_1_3_4_3_2","doi-asserted-by":"crossref","first-page":"2702","DOI":"10.1101\/gad.915701","article-title":"Tissue-specific GATA factors are transcriptional effectors of the small GTPase RhoA","volume":"15","author":"Charron F","year":"2001","unstructured":"F Charron, et al., Tissue-specific GATA factors are transcriptional effectors of the small GTPase RhoA. Genes Dev 15, 2702\u20132719 (2001).","journal-title":"Genes Dev"},{"key":"e_1_3_4_4_2","doi-asserted-by":"crossref","first-page":"13752","DOI":"10.1074\/jbc.M105736200","article-title":"Distinct roles of mitogen-activated protein kinase pathways in GATA-4 transcription factor-mediated regulation of B-type natriuretic peptide gene","volume":"277","author":"Kerkel\u00e4 R","year":"2002","unstructured":"R Kerkel\u00e4, S Pikkarainen, T Majalahti-Palviainen, H Tokola, H Ruskoaho, Distinct roles of mitogen-activated protein kinase pathways in GATA-4 transcription factor-mediated regulation of B-type natriuretic peptide gene. J Biol Chem 277, 13752\u201313760 (2002).","journal-title":"J Biol Chem"},{"key":"e_1_3_4_5_2","doi-asserted-by":"crossref","first-page":"7460","DOI":"10.1128\/MCB.21.21.7460-7469.2001","article-title":"The transcription factor GATA4 is activated by extracellular signal-regulated kinase 1- and 2-mediated phosphorylation of serine 105 in cardiomyocytes","volume":"21","author":"Liang Q","year":"2001","unstructured":"Q Liang, et al., The transcription factor GATA4 is activated by extracellular signal-regulated kinase 1- and 2-mediated phosphorylation of serine 105 in cardiomyocytes. Mol Cell Biol 21, 7460\u20137469 (2001).","journal-title":"Mol Cell Biol"},{"key":"e_1_3_4_6_2","doi-asserted-by":"crossref","first-page":"13721","DOI":"10.1074\/jbc.275.18.13721","article-title":"Phosphorylation of GATA-4 is involved in alpha 1-adrenergic agonist-responsive transcription of the endothelin-1 gene in cardiac myocytes","volume":"275","author":"Morimoto T","year":"2000","unstructured":"T Morimoto, et al., Phosphorylation of GATA-4 is involved in alpha 1-adrenergic agonist-responsive transcription of the endothelin-1 gene in cardiac myocytes. J Biol Chem 275, 13721\u201313726 (2000).","journal-title":"J Biol Chem"},{"key":"e_1_3_4_7_2","doi-asserted-by":"crossref","first-page":"38949","DOI":"10.1074\/jbc.R000029200","article-title":"The zinc finger-containing transcription factors GATA-4, -5, and -6. Ubiquitously expressed regulators of tissue-specific gene expression","volume":"275","author":"Molkentin JD","year":"2000","unstructured":"JD Molkentin, The zinc finger-containing transcription factors GATA-4, -5, and -6. Ubiquitously expressed regulators of tissue-specific gene expression. J Biol Chem 275, 38949\u201338952 (2000).","journal-title":"J Biol Chem"},{"key":"e_1_3_4_8_2","doi-asserted-by":"crossref","first-page":"24852","DOI":"10.1074\/jbc.M314317200","article-title":"Mitogen-activated protein kinases p38 and ERK 1\/2 mediate the wall stress-induced activation of GATA-4 binding in adult heart","volume":"279","author":"Tenhunen O","year":"2004","unstructured":"O Tenhunen, et al., Mitogen-activated protein kinases p38 and ERK 1\/2 mediate the wall stress-induced activation of GATA-4 binding in adult heart. 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Pflugers Arch 443, 362\u2013369 (2002).","journal-title":"Pflugers Arch"},{"key":"e_1_3_4_11_2","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1161\/01.CIR.103.5.730","article-title":"Pressure overload increases GATA4 binding activity via endothelin-1","volume":"103","author":"Hautala N","year":"2001","unstructured":"N Hautala, et al., Pressure overload increases GATA4 binding activity via endothelin-1. Circulation 103, 730\u2013735 (2001).","journal-title":"Circulation"},{"key":"e_1_3_4_12_2","doi-asserted-by":"crossref","first-page":"6341","DOI":"10.1093\/emboj\/19.23.6341","article-title":"The MEK1-ERK1\/2 signaling pathway promotes compensated cardiac hypertrophy in transgenic mice","volume":"19","author":"Bueno OF","year":"2000","unstructured":"OF Bueno, et al., The MEK1-ERK1\/2 signaling pathway promotes compensated cardiac hypertrophy in transgenic mice. EMBO J 19, 6341\u20136350 (2000).","journal-title":"EMBO J"},{"key":"e_1_3_4_13_2","doi-asserted-by":"crossref","first-page":"1048","DOI":"10.1101\/gad.11.8.1048","article-title":"GATA4 transcription factor is required for ventral morphogenesis and heart tube formation","volume":"11","author":"Kuo CT","year":"1997","unstructured":"CT Kuo, et al., GATA4 transcription factor is required for ventral morphogenesis and heart tube formation. Genes Dev 11, 1048\u20131060 (1997).","journal-title":"Genes Dev"},{"key":"e_1_3_4_14_2","doi-asserted-by":"crossref","first-page":"1061","DOI":"10.1101\/gad.11.8.1061","article-title":"Requirement of the transcription factor GATA4 for heart tube formation and ventral morphogenesis","volume":"11","author":"Molkentin JD","year":"1997","unstructured":"JD Molkentin, Q Lin, SA Duncan, EN Olson, Requirement of the transcription factor GATA4 for heart tube formation and ventral morphogenesis. 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Genesis 47, 688\u2013696 (2009).","journal-title":"Genesis"},{"key":"e_1_3_4_23_2","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1172\/JCI40295","article-title":"Cardiac fibroblasts are essential for the adaptive response of the murine heart to pressure overload","volume":"120","author":"Takeda N","year":"2010","unstructured":"N Takeda, et al., Cardiac fibroblasts are essential for the adaptive response of the murine heart to pressure overload. J Clin Invest 120, 254\u2013265 (2010).","journal-title":"J Clin Invest"},{"key":"e_1_3_4_24_2","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1016\/j.yjmcc.2008.12.010","article-title":"Cardiac interstitial cells express GATA4 and control dedifferentiation and cell cycle re-entry of adult cardiomyocytes","volume":"46","author":"Zaglia T","year":"2009","unstructured":"T Zaglia, et al., Cardiac interstitial cells express GATA4 and control dedifferentiation and cell cycle re-entry of adult cardiomyocytes. J Mol Cell Cardiol 46, 653\u2013662 (2009).","journal-title":"J Mol Cell Cardiol"},{"key":"e_1_3_4_25_2","doi-asserted-by":"crossref","first-page":"3198","DOI":"10.1172\/JCI32573","article-title":"Cardiomyocyte GATA4 functions as a stress-responsive regulator of angiogenesis in the murine heart","volume":"117","author":"Heineke J","year":"2007","unstructured":"J Heineke, et al., Cardiomyocyte GATA4 functions as a stress-responsive regulator of angiogenesis in the murine heart. J Clin Invest 117, 3198\u20133210 (2007).","journal-title":"J Clin Invest"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.1104499108","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,6,7]],"date-time":"2022-06-07T03:55:09Z","timestamp":1654574109000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.1104499108"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2011,7,11]]},"references-count":25,"journal-issue":{"issue":"30","published-print":{"date-parts":[[2011,7,26]]}},"alternative-id":["10.1073\/pnas.1104499108"],"URL":"https:\/\/doi.org\/10.1073\/pnas.1104499108","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2011,7,11]]},"assertion":[{"value":"2011-07-11","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}