title: Anti-apoptotic function of the E2F transcription factor 4 (E2F4)/p130, a member of retinoblastoma gene family in cardiac myocytes.
abstract: The E2F4-p130 transcriptional repressor complex is a cell-cycle inhibitor in mitotic cells. However, the role of E2F4/p130 in differentiated cells is largely unknown. We investigated the role of E2F4/p130 in the regulation of apoptosis in postmitotic cardiomyocytes. Here we demonstrate that E2F4 can inhibit hypoxia-induced cell death in isolated ventricular cardiomyocytes. As analyzed by chromatin immunoprecipitation, the E2F4-p130-repressor directly blocks transcription of essential apoptosis-related genes, E2F1, Apaf-1, and p73α through recruitment of histone deacetylase 1 (HDAC1). In contrast, diminution of the E2F4-p130-HDAC1-repressor and recruitment of E2F1 and histone acetylase activity to these E2F-regulated promoters is required for the execution of cell death. Expression of kinase-dead HDAC1.H141A or HDAC-binding deficient p130ΔHDAC1 abolishes the antiapoptotic effect of E2F4. Moreover, histological examination of E2F4(-/-) hearts revealed a markedly enhanced degree of cardiomyocyte apoptosis. Taken together, our genetic and biochemical data delineate an essential negative function of E2F4 in cardiac myocyte apoptosis.
authors.affiliation: University Health Network, Toronto, Canada. ddingar@uhnresearch.ca
authors.forename: Dharmendra
authors.initials: D
authors.lastname: Dingar
authors.forename: Filip
authors.initials: F
authors.lastname: Konecny
authors.forename: Jian
authors.initials: J
authors.lastname: Zou
authors.forename: Xuetao
authors.initials: X
authors.lastname: Sun
authors.forename: Rüdiger
authors.initials: R
authors.lastname: von Harsdorf
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D050687:E2F1 Transcription Factor / Q000235:genetics; D050704:E2F4 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D056284:Histone Deacetylase 1 / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D021381:Protein Transport; D051381:Rats
chemical_list: D050687:E2F1 Transcription Factor; D050704:E2F4 Transcription Factor; D056284:Histone Deacetylase 1