Akt deficiency impairs normal cell proliferation and suppresses oncogenesis in a p53-independent and mTORC1-dependent manner
Akt deficiency impairs normal cell proliferation and suppresses oncogenesis in a p53-independent and mTORC1-dependent manner
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DOI：
10.1016/j.ccr.2006.08.022
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发表时间：
2006-10-01
期刊：
影响因子：
50.3
通讯作者：
Hay, Nissim
中科院分区：
文献类型：
--
作者：
Skeen, Jennifer E.;Bhaskar, Prashanth T.;Hay, Nissim
Akt通过抑制细胞凋亡参与肿瘤发生。在这里，我们确定Akt是正常细胞增殖和肿瘤易感性所必需的，独立于其抗凋亡活性。通过删除Akt 1部分消除Akt活性抑制细胞增殖和肿瘤发生。这些效应通过删除Akt 1和Akt 2而复合。在体内，Akt 1基因敲除小鼠对MMTV-v-H-Ras诱导的肿瘤和皮肤癌变具有抗性。因此，Akt活性的部分消融足以在体外和体内抑制肿瘤发生。Akt缺陷对细胞增殖和肿瘤发生的影响是p53非依赖性的，但依赖于mTORC 1。令人惊讶的是，在mTORC 1过度激活时，Akt活性的降低不会损害细胞增殖和致癌转化的易感性;因此，Akt可能仅通过mTORC 1介导这些过程。
Akt contributes to tumorigenesis by inhibiting apoptosis. Here We establish that Akt is required for normal cell proliferation and susceptibility to oncogenesis independently of its antiapoptotic activity. Partial ablation of Akt activity by deleting Akt1 inhibits cell proliferation and oncogenesis. These effects are compounded by deleting both Akt1 and Akt2. In vivo, Akt1 null mice are resistant to MMTV-v-H-Ras-induced tumors and to skin carcinogenesis. Thus, partial ablation of Akt activity is sufficient to suppress tumorigenesis in vitro and in vivo. The effect of Akt deficiency on cell proliferation and oncogenesis is p53 independent but mTORC1 dependent. Surprisingly, upon mTORC1 hyperactivation, the reduction in Akt activity does not impair cell proliferation and susceptibility to oncogenic transformation; thus, Akt may mediate these processes exclusively via mTORC1.