University Health Network, Toronto, Canada.
J Mol Cell Cardiol. 2012 Dec;53(6):820-8. doi: 10.1016/j.yjmcc.2012.09.004. Epub 2012 Sep 15.
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.
E2F4-p130 转录抑制复合物是有丝分裂细胞中的细胞周期抑制剂。然而，E2F4/p130 在分化细胞中的作用在很大程度上是未知的。我们研究了 E2F4/p130 在有丝分裂后心肌细胞凋亡调控中的作用。在这里，我们证明 E2F4 可以抑制分离的心室心肌细胞中缺氧诱导的细胞死亡。通过染色质免疫沉淀分析，E2F4-p130 抑制剂通过募集组蛋白去乙酰化酶 1（HDAC1），直接阻断与细胞凋亡相关的必需基因 E2F1、Apaf-1 和 p73α 的转录。相比之下，E2F4-p130-HDAC1 抑制剂的减少以及 E2F1 和组蛋白乙酰化酶活性向这些 E2F 调节的启动子的募集，是细胞死亡执行所必需的。表达激酶失活的 HDAC1.H141A 或缺乏 HDAC 结合能力的 p130ΔHDAC1 会消除 E2F4 的抗凋亡作用。此外，E2F4(-/-) 心脏的组织学检查显示心肌细胞凋亡的程度明显增强。总之，我们的遗传和生化数据描绘了 E2F4 在心肌细胞凋亡中的重要负调控功能。
