STABILIZATION OF THE P53 TUMOR SUPPRESSOR IS INDUCED BY ADENOVIRUS-5 E1A AND ACCOMPANIES APOPTOSIS
STABILIZATION OF THE P53 TUMOR SUPPRESSOR IS INDUCED BY ADENOVIRUS-5 E1A AND ACCOMPANIES APOPTOSIS
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DOI：
10.1101/gad.7.4.535
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发表时间：
1993-04-01
影响因子：
10.5
通讯作者：
RULEY, HE
中科院分区：
文献类型：
--
作者：
LOWE, SW;RULEY, HE
人腺病毒的致癌转化需要1A和1B早期区（E1A和E1B），并提供了一个多步骤致癌的模型。这项研究表明，在腺病毒5 （Ad5）转化细胞中观察到的p53代谢稳定可以发生在单独表达EIA的未转化细胞中。稳定型p53定位于细胞核，与野生型p53在与hsc70、PAb420、Ad5 p55E1B和SV40大T抗原的相互作用方面没有区别。此外，结合Ad5 p55E1B或SV40大T抗原对p53水平或转换没有额外的影响。在转移E1A基因后40小时内，多种细胞类型中p53水平也会升高。E1A也通过类似凋亡的过程导致细胞失去活力。凋亡似乎与p53有关，因为在失去E1A的存活细胞中，p53水平恢复正常，而E1B保护细胞免受E1A的毒性作用。这些结果表明：(1)p53参与肿瘤抑制和/或细胞凋亡可以在蛋白转换水平上进行调节；(2)E1B的主要致癌作用是对抗细胞对E1A的反应（即p53的稳定和相关的细胞凋亡），这种反应阻止了E1A单独转化。这代表了第一个高水平的内源性p53在响应致癌挑战时被诱导的生理环境，具有抑制转化的明显后果。
Oncogenic transformation by human adenoviruses requires early regions 1A and 1B (E1A and E1B) and provides a model of multistep carcinogenesis. This study shows that the metabolic stabilization of p53 observed in adenovirus 5 (Ad5)-transformed cells can occur in untransformed cells expressing EIA alone. Stabilized p53 was localized to the nucleus and was indistinguishable from wild-type p53 with respect to its interactions with hsc70, PAb420, Ad5 p55E1B, and SV40 large T antigen. Moreover, binding of Ad5 p55E1B or SV40 large T antigen had no additional effect on p53 levels or turnover. Higher levels of p53 were also induced in a variety of cell types within 40 hr after transferring E1A genes. E1A also caused cells to lose viability by a process resembling apoptosis. The apoptosis appeared to involve p53, because p53 levels reverted to normal in surviving cells that had lost E1A, and E1B protected cells from the toxic effects of E1A. These results suggest that (1) the involvement of p53 in tumor suppression and/or apoptosis can be regulated at the level of protein turnover, and (2) a major oncogenic role for E1B is to counter cellular responses to E1A (i.e., stabilization of p53 and associated apoptosis) that preclude transformation by E1A alone. This represents the first physiological setting in which high levels of endogenous p53 are induced in response to an oncogenic challenge, with the apparent consequence of suppressing transformation.