Activation of Cdc2 contributes to apoptosis in HPV E6 expressing human keratinocytes in response to therapeutic agents.
Activation of Cdc2 contributes to apoptosis in HPV E6 expressing human keratinocytes in response to therapeutic agents.
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Cdc2 的激活有助于表达 HPV E6 的人角质形成细胞响应治疗剂而发生凋亡。
DOI：
10.1016/j.jmb.2007.09.031
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发表时间：
2007
影响因子：
5.6
通讯作者：
Chen,JasonJ
中科院分区：
文献类型：
--
作者：
Liu,Zhi-Guo;Zhao,Li-Na;Liu,Ying-Wang;Li,Ting-Ting;Fan,Dai-Ming;Chen,JasonJ
人乳头瘤病毒 (HPV) 感染与宫颈癌的发生密切相关。 HPV E6癌基因可诱导宫颈癌前驱病变细胞凋亡，但其机制尚不清楚。虽然预计 E6 使 p53 失活会导致细胞凋亡减少，但在某些实验条件下，E6 也会使细胞对细胞凋亡敏感。在这里，我们证明 E6 在人角质形成细胞中的表达导致对化疗药物的敏感性。细胞死亡被证明是由涉及半胱天冬酶激活和线粒体途径的细胞凋亡引起的。为了探索 E6 表达细胞对细胞凋亡敏感的机制，我们使用蛋白质组学方法来鉴定 E6 表达细胞和对照角质形成细胞中差异表达的蛋白质。在检测的近千种蛋白质中，Cdc2 被证明是 E6 表达细胞中上调最显着的蛋白质。 p53 降解似乎对于 E6 上调 Cdc2 很重要。使用遗传、药理学和 siRNA 策略，证明了 Cdc2 在 E6 表达引起的细胞凋亡中的作用。因此，这些结果对于增强化疗功效具有重要的治疗意义。
Infection with human papillomaviruses (HPV) is strongly associated with the development of cervical cancer. The HPV E6 oncogene induces apoptosis in cervical cancer precursor lesions but the mechanism is poorly understood. While it is expected that inactivation of p53 by E6 should lead to a reduction in apoptosis, E6 also sensitizes cells to apoptosis under some experimental conditions. Here, we demonstrate that expression of E6 in human keratinocytes rendered sensitization to chemotherapeutic agents. The cell death was shown to be by apoptosis involving caspase activation and the mitochondria pathway. To explore mechanisms involved in sensitization of E6 expressing cells to apoptosis, we used a proteomic approach to identify proteins differentially expressed in E6 expressing and control keratinocytes. Among nearly a thousand proteins examined, Cdc2 was demonstrated to be the most dramatically up-regulated protein in E6 expressing cells. p53 degradation appears to be important for the up-regulation of Cdc2 by E6. Using genetic, pharmacologic, and siRNA strategies, a role for Cdc2 in E6 expression-conferred apoptosis was demonstrated. Thus, these results have important therapeutic implications in enhancing the efficacy of chemotherapy.