Up-regulation of Bcl-2 homology 3 (BH3)-only proteins by E2F1 mediates apoptosis
Up-regulation of Bcl-2 homology 3 (BH3)-only proteins by E2F1 mediates apoptosis
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DOI：
10.1074/jbc.m312866200
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发表时间：
2004-03-05
影响因子：
4.8
通讯作者：
Ginsberg, D
中科院分区：
文献类型：
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作者：
Hershko, T;Ginsberg, D
E2F1转录因子是肿瘤抑制基因pRb的关键下游靶点。视网膜母细胞瘤(retinoblastoma，RB)通路在人类肿瘤中经常失活，导致E2F活性失控，从而同时诱导细胞增殖和凋亡。BCL-2同源3(BH3)-Only蛋白是BCL-2蛋白家族中促凋亡的成员，可在不同刺激下触发细胞凋亡。我们在这里表明，E2F1通过直接的转录机制上调促凋亡的BH3蛋白PUMA、NOXA、Bim和HRK/DP5的表达。HPV16E7蛋白的表达破坏了RB/E2F复合体，也上调了这四种仅BH3蛋白的表达，暗示内源性E2F参与了这一现象。事实上，内源性E2F1结合了这四个基因的启动子。此外，抑制E2F1诱导的NOXA或PUMA的表达导致E2F1诱导的细胞凋亡显著减少，表明NOXA和PUMA水平的增加介导了E2F1诱导的细胞凋亡。重要的是，抑制E2F活性可以消除DNA损伤引起的PUMA水平的升高，暗示E2F参与了PUMA表达的生理调节。这些数据提供了E2F和凋亡机制之间的新的直接联系，并可能解释Rb/E2F途径缺陷的细胞对化疗敏感性增加的原因。
The E2F1 transcription factor is a critical downstream target of the tumor suppressor pRB. The retinoblastoma (RB) pathway is often inactivated in human tumors, resulting in deregulated E2F activity that can induce both proliferation and apoptosis. Bcl-2 homology 3 (BH3)-only proteins are pro-apoptotic members of the Bcl-2 protein family that trigger apoptosis in response to diverse stimuli. We show here that E2F1 up-regulates the expression of the pro-apoptotic BH3-only proteins PUMA, Noxa, Bim, and Hrk/DP5 through a direct transcriptional mechanism. Expression of the E7 protein of HPV16, which disrupts RB/E2F complexes, also up-regulates the expression of these four BH3-only proteins, implicating endogenous E2F in this phenomenon. Indeed, endogenous E2F1 binds the promoters of these four genes. Furthermore, inhibition of E2F1-induced expression of either Noxa or PUMA results in a significant reduction in E2F1-induced apoptosis, indicating that increased Noxa and PUMA levels mediate this E2F1-induced apoptosis. Importantly, inhibition of E2F activity abolishes DNA damage-induced elevation of PUMA levels, implicating E2F in the physiological regulation of PUMA expression. These data provide a novel direct link between E2F and the apoptotic machinery and may explain the increased sensitivity of cells with a defective RB/E2F pathway to chemotherapy.