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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Complete switch from Mdm2 to human papillomavirus E6-mediated degradation of p53 in cervical cancer cells
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Complete switch from Mdm2 to human papillomavirus E6-mediated degradation of p53 in cervical cancer cells

机译：从Mdm2完全转换为人乳头瘤病毒E6介导的宫颈癌细胞p53降解

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摘要

The E6 oncoprotein of human papillomaviruses (HPVs) that are associated with cervical cancer utilizes the cellular ubiquitin- protein ligase E6-AP to target the tumor suppressor p53 for degradation. In normal cells (i.e., in the absence of E6), p53 is also a target of the ubiquitin--proteasome pathway. Under these con- ditions, however, p53 degradation is mediated by Mdm2 rather than by E6-AP. Here we show in a mutational analysis that, surprisingly, the structural requirements of p53 to serve as a proteolytic substrate differ between E6 proteins derived from different HPV types and. as expected. between Mdm2 and E6 proteins in vitro and in vivo. Stable expression of such mutants in HPV-negative and HPV-positive cell lines demonstrates that in HPV-positive cancer cells, the E6-dependent pathway of p53 deg- radation is not only active but, moreover, is required for degra- dation of p53, whereas the Mdm2-dependent pathway is inactive. Because the p53 pathway was reported to be functional in HPV- positive cancer cells. this finding indicates clearly that the ability of the E6 oncoprotein to target p53 for degradation is required for the growth of HPV-positive cancer cells.
机译：与宫颈癌相关的人乳头瘤病毒（HPV）的E6癌蛋白利用细胞泛素蛋白连接酶E6-AP靶向肿瘤抑制因子p53进行降解。在正常细胞中（即在没有E6的情况下），p53也是泛素-蛋白酶体途径的靶标。然而，在这些条件下，p53降解是由Mdm2而不是由E6-AP介导的。在这里，我们通过突变分析表明，令人惊讶的是，p53作为蛋白水解底物的结构要求在衍生自不同HPV类型的E6蛋白之间有所不同。如预期的那样。体内和体外Mdm2和E6蛋白之间此类突变体在HPV阴性和HPV阳性细胞系中的稳定表达表明，在HPV阳性癌细胞中，p53降解的E6依赖性途径不仅是活跃的，而且是p53降解所必需的，而依赖Mdm2的途径则是无效的。因为据报道p53途径在HPV阳性癌细胞中起作用。这一发现清楚地表明，HPV阳性癌细胞的生长需要E6癌蛋白靶向p53降解的能力。

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