Regulation of the activity of p38 mitogen-activated protein kinase by Akt in cancer and adenoviral protein E1A-mediated sensitization to apoptosis
Regulation of the activity of p38 mitogen-activated protein kinase by Akt in cancer and adenoviral protein E1A-mediated sensitization to apoptosis
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DOI：
10.1128/mcb.23.19.6836-6848.2003
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发表时间：
2003-10-01
影响因子：
5.3
通讯作者：
Hung, MC
中科院分区：
文献类型：
--
作者：
Liao, Y;Hung, MC
腺病毒早期区1A （E1A）蛋白介导对不同刺激诱导的细胞凋亡的致敏，如肿瘤坏死因子α、紫外线和伽马辐射以及不同种类的抗癌药物。然而，e1a介导的细胞凋亡致敏的分子机制仍未完全明确。本研究表明，e1a介导的细胞凋亡致敏作用是通过关键存活因子Akt的失活和促凋亡因子p38的激活实现的。此外，通过特异性抑制剂或基因敲除Akt1导致Akt失活，可能通过释放p38上游激酶的活性，包括ASK1和MEKK3，导致p38活化。此外，我们发现p38磷酸化在多种人类肿瘤组织中下调，Akt磷酸化在人类乳腺癌中上调，这与肿瘤分期有关。E1A保守结构域的缺失突变是E1A诱导的Akt活性下调所必需的，它破坏了E1A介导的p38活性上调，也消除了E1A介导的化学致敏作用。因此，p38的激活和Akt的失活可能对肿瘤抑制和细胞凋亡敏感具有普遍意义。
The adenoviral early region 1A (E1A) protein mediates sensitization to different stimulus-induced apoptosis, such as tumor necrosis factor alpha, UV and gamma irradiation, and different categories of anticancer drugs. However, the molecular mechanisms underlying E1A-mediated sensitization to apoptosis are still not completely defined. Here, we show that E1A-mediated sensitization to apoptosis by the inactivation of a key survival factor Akt and the activation of a pro-apoptotic factor p38. Also, inactivation of Akt by either a specific inhibitor or a genetic knockout of Akt1 results in p38 activation, possibly through the release of the activity of p38 upstream kinases, including ASK1 and MEKK3. In addition, we showed that p38 phosphorylation is downregulated and Akt phosphorylation is upregulated in multiple human tumor tissues, and this correlates with tumor stage in human breast cancer. A deletion mutation of a conserved domain of E1A, which is required for E1A-induced downregulation of Akt activity, disrupts E1A-mediated upregulation of p38 activity and also eliminates E1A-mediated chemosensitization. Thus, activation of p38 and inactivation of Akt may have general implications for tumor suppression and sensitization to apoptosis.