Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
Genes Dev. 2012 Jul 15;26(14):1546-57. doi: 10.1101/gad.196238.112.
Oncogene-induced senescence is an anti-proliferative stress response program that acts as a fail-safe mechanism to limit oncogenic transformation and is regulated by the retinoblastoma protein (RB) and p53 tumor suppressor pathways. We identify the atypical E2F family member E2F7 as the only E2F transcription factor potently up-regulated during oncogene-induced senescence, a setting where it acts in response to p53 as a direct transcriptional target. Once induced, E2F7 binds and represses a series of E2F target genes and cooperates with RB to efficiently promote cell cycle arrest and limit oncogenic transformation. Disruption of RB triggers a further increase in E2F7, which induces a second cell cycle checkpoint that prevents unconstrained cell division despite aberrant DNA replication. Mechanistically, E2F7 compensates for the loss of RB in repressing mitotic E2F target genes. Together, our results identify a causal role for E2F7 in cellular senescence and uncover a novel link between the RB and p53 pathways.
癌基因诱导的衰老（Oncogene-induced senescence）是一种抗增殖应激反应程序，作为一种失效保护机制，可限制致癌转化，并受视网膜母细胞瘤蛋白（RB）和 p53 肿瘤抑制途径调控。我们确定了非典型 E2F 家族成员 E2F7 是癌基因诱导衰老过程中唯一被强烈上调的 E2F 转录因子，在这种情况下，它作为 p53 的直接转录靶标发挥作用。E2F7 一旦被诱导，就会结合并抑制一系列 E2F 靶基因，并与 RB 合作，有效地促进细胞周期停滞并限制致癌转化。RB 的破坏会引发 E2F7 的进一步增加，从而诱导第二个细胞周期检查点，尽管存在异常的 DNA 复制，但仍能阻止不受限制的细胞分裂。从机制上讲，E2F7 通过抑制有丝分裂 E2F 靶基因来弥补 RB 的缺失。总之，我们的研究结果确定了 E2F7 在细胞衰老中的因果作用，并揭示了 RB 和 p53 途径之间的新联系。
