Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, China.
EMBO J. 2013 Aug 14;32(16):2204-16. doi: 10.1038/emboj.2013.133. Epub 2013 Jun 7.
The primary role of autophagy is adaption to starvation. However, increasing evidence suggests that autophagy inhibition also plays an important role in tumorigenesis. Upregulation of X-linked inhibitor of apoptosis (XIAP) has been associated to a variety of human cancers, yet the underlying mechanisms remain obscure. Here, we report that XIAP suppresses autophagy by exerting a previously unidentified ubiquitin E3 ligase activity towards Mdm2, which is a negative regulator of p53. XIAP controls serum starvation-induced autophagy downstream of the PI3K/Akt pathway. In mouse models, inhibition of autophagy by XIAP promotes tumorigenecity of HCT116 cells. XIAP-mediated autophagy inhibition is also largely validated in clinical tumour samples. These findings reveal a novel XIAP-Mdm2-p53 pathway that mediates the inhibition of autophagy, by which XIAP may contribute to tumorigenesis.
自噬的主要作用是适应饥饿。然而，越来越多的证据表明，自噬抑制在肿瘤发生中也起着重要作用。凋亡抑制因子 X（XIAP）的上调与多种人类癌症有关，但潜在的机制尚不清楚。在这里，我们报告 XIAP 通过对 Mdm2 发挥以前未被识别的泛素 E3 连接酶活性来抑制自噬，Mdm2 是 p53 的负调节剂。XIAP 通过 PI3K/Akt 通路调控血清饥饿诱导的自噬。在小鼠模型中，XIAP 抑制自噬促进 HCT116 细胞的致瘤性。XIAP 介导的自噬抑制在临床肿瘤样本中也得到了广泛验证。这些发现揭示了一种新的 XIAP-Mdm2-p53 通路，该通路介导自噬的抑制，XIAP 可能通过该通路促进肿瘤发生。
