Department of Oncological Sciences, Mount Sinai School of Medicine, New York, New York 10029, USA.
Genes Dev. 2012 Jul 15;26(14):1533-45. doi: 10.1101/gad.184911.111.
The p53 tumor suppressor protein is a transcription factor that exerts its effects on the cell cycle via regulation of gene expression. Although the mechanism of p53-dependent transcriptional activation has been well-studied, the molecular basis for p53-mediated repression has been elusive. The E2F family of transcription factors has been implicated in regulation of cell cycle-related genes, with E2F6, E2F7, and E2F8 playing key roles in repression. In response to cellular DNA damage, E2F7, but not E2F6 or E2F8, is up-regulated in a p53-dependent manner, with p53 being sufficient to increase expression of E2F7. Indeed, p53 occupies the promoter of the E2F7 gene after genotoxic stress, consistent with E2F7 being a novel p53 target. Ablation of E2F7 expression abrogates p53-dependent repression of a subset of its targets, including E2F1 and DHFR, in response to DNA damage. Furthermore, E2F7 occupancy of the E2F1 and DHFR promoters is detected, and expression of E2F7 is sufficient to inhibit cell proliferation. Taken together, these results show that p53-dependent transcriptional up-regulation of its target, E2F7, leads to repression of relevant gene expression. In turn, this E2F7-dependent mechanism contributes to p53-dependent cell cycle arrest in response to DNA damage.
p53 肿瘤抑制蛋白是一种转录因子，通过调节基因表达对细胞周期发挥作用。虽然 p53 依赖性转录激活的机制已经得到很好的研究，但 p53 介导的抑制的分子基础仍然难以捉摸。E2F 家族转录因子参与细胞周期相关基因的调节，E2F6、E2F7 和 E2F8 在抑制中发挥关键作用。在细胞 DNA 损伤的情况下，E2F7（而不是 E2F6 或 E2F8）以 p53 依赖性方式上调，p53 足以增加 E2F7 的表达。事实上，p53 在基因毒性应激后占据 E2F7 基因的启动子，这与 E2F7 是一种新的 p53 靶标一致。E2F7 表达的缺失消除了 p53 依赖性对其靶标（包括 E2F1 和 DHFR）的抑制，以响应 DNA 损伤。此外，检测到 E2F7 占据 E2F1 和 DHFR 启动子的位置，并且 E2F7 的表达足以抑制细胞增殖。总之，这些结果表明，p53 依赖性转录激活其靶标 E2F7 导致相关基因表达的抑制。反过来，这种 E2F7 依赖性机制有助于 p53 依赖性细胞周期停滞对 DNA 损伤的反应。
