PML isoforms IV and V contribute to adenovirus-mediated oncogenic transformation by functionally inhibiting the tumor-suppressor p53
PML isoforms IV and V contribute to adenovirus-mediated oncogenic transformation by functionally inhibiting the tumor-suppressor p53
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DOI：
10.1038/onc.2015.63
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发表时间：
2016-01
期刊：
影响因子：
8
通讯作者：
P. Wimmer;J. Berscheminski;P. Blanchette;P. Groitl;P. Branton;Ronald T. Hay;T. Dobner;S. Schreiner
中科院分区：
文献类型：
--
作者：
P. Wimmer;J. Berscheminski;P. Blanchette;P. Groitl;P. Branton;Ronald T. Hay;T. Dobner;S. Schreiner
尽管细胞肿瘤抑制因子 p53 的调节被认为在 E1A/E1B-55K 介导的肿瘤发生中起主要作用，但其他早幼粒细胞白血病核体 (PML-NB)/PML 致癌结构域 (POD) 相关因子（包括 SUMO、Mre11、Daxx）以及这些核体的完整性也有助于转化过程。然而，SUMO 依赖性 PML-IV 和 PML-V 相互作用对 PML 相关 E1B-55K 的生化后果和致癌性改变迄今为止仍然难以捉摸。我们进行了突变分析来定义 E1B-55K 多肽内的 PML 相互作用基序。我们的结果表明，p53、Mre11 和 Daxx 相互作用不需要 E1B-55K/PML 结合。我们还观察到，由于 PML-IV 或 PML-V 结合缺陷而缺乏亚核 PML 定位的 E1B-55K 不再能够介导 E1B-55K 依赖性 p53 SUMO 化、抑制 p53 介导的反式激活或有效转化原代啮齿动物细胞。这些结果以及 p53 的 E1B-55K 依赖性 SUMO 化是有效细胞转化所必需的观察结果，为 E1B-55K 病毒癌蛋白的 SUMO 连接酶活性与其促进生长的致癌活性密切相关的观点提供了证据。
Although modulation of the cellular tumor-suppressor p53 is considered to have the major role in E1A/E1B-55K-mediated tumorigenesis, other promyelocytic leukemia nuclear body (PML-NB)/PML oncogenic domain (POD)-associated factors including SUMO, Mre11, Daxx, as well as the integrity of these nuclear bodies contribute to the transformation process. However, the biochemical consequences and oncogenic alterations of PML-associated E1B-55K by SUMO-dependent PML-IV and PML-V interaction have so far remained elusive. We performed mutational analysis to define a PML interaction motif within the E1B-55K polypeptide. Our results showed that E1B-55K/PML binding is not required for p53, Mre11 and Daxx interaction. We also observed that E1B-55K lacking subnuclear PML localization because of either PML-IV or PML-V-binding deficiency was no longer capable of mediating E1B-55K-dependent SUMOylation of p53, inhibition of p53-mediated transactivation or efficiently transforming primary rodent cells. These results together with the observation that E1B-55K-dependent SUMOylation of p53 is required for efficient cell transformation, provides evidence for the idea that the SUMO ligase activity of the E1B-55K viral oncoprotein is intimately linked to its growth-promoting oncogenic activities.