Sp100A is a tumor suppressor that activates p53-dependent transcription and counteracts E1A/E1B-55K-mediated transformation
Sp100A is a tumor suppressor that activates p53-dependent transcription and counteracts E1A/E1B-55K-mediated transformation
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DOI：
10.1038/onc.2015.378
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发表时间：
2016-06-16
期刊：
影响因子：
8
通讯作者：
Schreiner, S.
中科院分区：
文献类型：
--
作者：
Berscheminski, J.;Brun, J.;Schreiner, S.
人腺病毒（HAdV）被用作研究哺乳动物细胞中的致瘤过程的模型系统，其中病毒癌蛋白E1 A和E1 B-55 K是致瘤转化绝对需要的，因为它们同时加速细胞周期进展并抑制肿瘤抑制蛋白如p53，尽管其潜在机制仍不清楚。在我们目前的研究中，我们提供的证据表明，E1 B-55 K结合PML-NB组件Sp100 A显然有一个重要的作用，在调节腺病毒介导的转化过程。具体地说，当E1 B-55 K/Sp100 A复合物募集p53时，Sp100 A诱导的p53转录活性的激活被有效地消除。因此，Sp100 A不仅通过稳定p53反式激活，而且通过抑制E1 A/E1 B-55 K介导的转化而表现出肿瘤抑制活性。E1 B-55 K抵消这种抑制活性，诱导Sp100 A SUMO化并将修饰的细胞因子隔离到细胞核的不溶性基质或细胞质内含物中。这些观察结果提供了新的见解如何E1 B-55 K调节细胞决定因素，以保持在致癌过程和裂解性感染的促生长活性。
Human adenoviruses (HAdV) are used as a model system to investigate tumorigenic processes in mammalian cells where the viral oncoproteins E1A and E1B-55K are absolutely required for oncogenic transformation, because they simultaneously accelerate cell cycle progression and inhibit tumor suppressor proteins such as p53, although the underlying mechanism is still not understood in detail. In our present study, we provide evidence that E1B-55K binding to the PML-NB component Sp100A apparently has an essential role in regulating adenovirus-mediated transformation processes. Specifically, when this E1B-55K/Sp100A complex recruits p53, Sp100A-induced activation of p53 transcriptional activity is effectively abolished. Hence, Sp100A exhibits tumor-suppressive activity, not only by stabilizing p53 transactivation but also by depressing E1A/E1B-55K-mediated transformation. E1B-55K counteracts this suppressive activity, inducing Sp100A SUMOylation and sequestering the modified cellular factor into the insoluble matrix of the nucleus or into cytoplasmic inclusions. These observations provide novel insights into how E1B-55K modulates cellular determinants to maintain growth-promoting activity during oncogenic processes and lytic infection.