| 论文作者 |
Chen, M; Wang, KJJ; Han, Y; Yan, SK; Yuan, HR; Liu, QL; Li, L; Li, N; Zhu, HW; Lu, DY; Wang, KH; Liu, F; Luo, DK; Zhang, YX; Jiang, J; Li, DL; Zhang, L; Ji, HB; Zhou, H; Chen, Y; Qin, J; Gao, DM |
| 摘要 |
AKT kinase is a key regulator in cell metabolism and survival, and its activation is strictly modulated. Herein, we identify XAF1 (XIAP-associated factor) as a direct interacting protein of AKT1, which strongly binds the N-terminal region of AKT1 to block its K63-linked poly-ubiquitination and subsequent activation. Consistently, Xaf1 knockout causes AKT activation in mouse muscle and fat tissues and reduces body weight gain and insulin resistance induced by high-fat diet. Pathologically, XAF1 expression is low and anti -correlated with the phosphorylated p-T308-AKT signal in prostate cancer samples, and Xaf1 knockout stimulates the p-T308-AKT signal to accelerate spontaneous prostate tumorigenesis in mice with Pten heterozygous loss. And ectopic expression of wild-type XAF1, but not the cancer-derived P277L mutant, inhibits orthotopic tumorigenesis. We further identify Forkhead box O 1 (FOXO1) as a transcriptional regulator of XAF1, thus forming a negative feedback loop between AKT1 and XAF1. These results reveal an important intrinsic regulatory mechanism of AKT signaling. |
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