Skeen Jennifer E, Bhaskar Prashanth T, Chen Chia-Chen, Chen William S, Peng Xiao-ding, Nogueira Veronique, Hahn-Windgassen Annett, Kiyokawa Hiroaki, Hay Nissim
Department of Biochemistry and Molecular Genetics, University of Illinois, Chicago, Illinois 60607, USA.
Cancer Cell. 2006 Oct;10(4):269-80. doi: 10.1016/j.ccr.2006.08.022.
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.
Akt通过抑制细胞凋亡促进肿瘤发生。在此我们证实，Akt对于正常细胞增殖及肿瘤发生易感性是必需的，且与其抗凋亡活性无关。通过缺失Akt1部分消除Akt活性会抑制细胞增殖及肿瘤发生。同时缺失Akt1和Akt2会使这些效应更加明显。在体内，Akt1基因敲除小鼠对MMTV-v-H-Ras诱导的肿瘤及皮肤癌发生具有抗性。因此，部分消除Akt活性足以在体外和体内抑制肿瘤发生。Akt缺失对细胞增殖及肿瘤发生的影响不依赖于p53，但依赖于mTORC1。令人惊讶的是，在mTORC1过度激活时，Akt活性的降低并不损害细胞增殖及致癌转化易感性；因此，Akt可能仅通过mTORC1介导这些过程。
