Liao Yong, Hung Mien-Chie
Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Mol Cell Biol. 2003 Oct;23(19):6836-48. doi: 10.1128/MCB.23.19.6836-6848.2003.
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.
腺病毒早期区域1A（E1A）蛋白介导对不同刺激诱导的细胞凋亡的敏感性，如肿瘤坏死因子α、紫外线和γ射线照射，以及不同类别的抗癌药物。然而，E1A介导的细胞凋亡敏感性的分子机制仍未完全明确。在此，我们表明E1A通过关键生存因子Akt的失活和促凋亡因子p38的激活介导细胞凋亡敏感性。此外，通过特异性抑制剂或Akt1基因敲除使Akt失活会导致p38激活，可能是通过释放包括ASKI和MEKK3在内的p38上游激酶的活性。另外，我们发现p38磷酸化在多种人类肿瘤组织中下调，而Akt磷酸化上调，这与人类乳腺癌的肿瘤分期相关。E1A诱导的Akt活性下调所需的E1A保守结构域的缺失突变，破坏了E1A介导的p38活性上调，也消除了E1A介导的化学增敏作用。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性具有普遍意义。
