Repression of the Arf tumor suppressor by E2F3 is required for normal cell cycle kinetics
Repression of the Arf tumor suppressor by E2F3 is required for normal cell cycle kinetics
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DOI：
10.1101/gad.1196704
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发表时间：
2004-06-15
影响因子：
10.5
通讯作者：
Lees, JA
中科院分区：
文献类型：
--
作者：
Aslanian, A;Iaquinta, PJ;Lees, JA
肿瘤的发展取决于两个关键肿瘤抑制网络的失活：p16(Ink4a)-cycD/cdk4-pRB-E2F 和 p19(Arf)-mdm2-p53，它们调节细胞增殖和肿瘤监测反应。众所周知，这些网络相互交叉，但人们对其中的机制知之甚少。在这里，我们表明 E2F 在正常细胞和转化细胞中直接参与 Arf 的转录控制。这种发生的方式与经典 E2F 响应目标的调节显着不同。在野生型小鼠胚胎成纤维细胞 (MEF) 中，Arf 启动子被 E2F3 占据，而不是其他 E2F 家族成员。在静止细胞中，这一作用主要由 E2F3b 来完成，E2F3b 是一种 E2F3 亚型，其功能之前尚未确定。 E2f3 的缺失足以去抑制 Arf，从而触发 p53 的激活和 p21(Cip1) 的表达。因此，E2F3 是正常细胞中 p19(Arf)-p53 通路的关键抑制因子。与这一概念一致，Arf 突变抑制 E2f3 缺陷 MEF 中 p53 和 p21(Cip1) 的激活。 Arf 损失还可以挽救 E2f3(-/-) 细胞已知的细胞周期重入缺陷，这与经典 E2F 响应基因的适当激活的恢复相关。我们的数据还证明了 E2F 在 Arf 致癌激活中的直接作用。具体来说，我们观察到内源性激活 E2F、E2F1 和 E2F3a 被招募到 Arf 启动子。因此，不同的 E2F 复合物直接有助于 Arf 的正常抑制和致癌激活。我们认为，监测 E2F 水平和/或活性是 Arf 响应不适当但非正常细胞增殖能力的关键组成部分。
Tumor development is dependent upon the inactivation of two key tumor-suppressor networks, p16(Ink4a)-cycD/cdk4-pRB-E2F and p19(Arf)-mdm2-p53, that regulate cellular proliferation and the tumor surveillance response. These networks are known to intersect with one another, but the mechanisms are poorly understood. Here, we show that E2F directly participates in the transcriptional control of Arf in both normal and transformed cells. This occurs in a manner that is significantly different from the regulation of classic E2F-responsive targets. In wild-type mouse embryonic fibroblasts (MEFs), the Arf promoter is occupied by E2F3 and not other E2F family members. In quiescent cells, this role is largely fulfilled by E2F3b, an E2F3 isoform whose function was previously undetermined. E2f3 loss is sufficient to derepress Arf, triggering activation of p53 and expression of p21(Cip1). Thus, E2F3 is a key repressor of the p19(Arf)-p53 pathway in normal cells. Consistent with this notion, Arf mutation suppresses the activation of p53 and p21(Cip1) in E2f3-deficient MEFs. Arf loss also rescues the known cell cycle re-entry defect of E2f3(-/-) cells, and this correlates with restoration of appropriate activation of classic E2F-responsive genes. Our data also demonstrate a direct role for E2F in the oncogenic activation of Arf. Specifically, we observe recruitment of the endogenous activating E2Fs, E2F1, and E2F3a, to the Arf promoter. Thus, distinct E2F complexes directly contribute to the normal repression and oncogenic activation of Arf. We propose that monitoring of E2F levels and/or activity is a key component of Arf's ability to respond to inappropriate, but not normal cellular proliferation.