XIAP inhibits autophagy via XIAP-Mdm2-p53 signalling.
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.
Mesh Terms:
Animals, Autophagy, Blotting, Western, Cell Transformation, Neoplastic, HCT116 Cells, HEK293 Cells, Humans, Immunohistochemistry, Immunoprecipitation, Mice, Microscopy, Electron, Proto-Oncogene Proteins c-mdm2, RNA Interference, RNA, Small Interfering, Signal Transduction, Starvation, Tumor Cells, Cultured, Tumor Suppressor Protein p53, Ubiquitin-Protein Ligases, X-Linked Inhibitor of Apoptosis Protein
Animals, Autophagy, Blotting, Western, Cell Transformation, Neoplastic, HCT116 Cells, HEK293 Cells, Humans, Immunohistochemistry, Immunoprecipitation, Mice, Microscopy, Electron, Proto-Oncogene Proteins c-mdm2, RNA Interference, RNA, Small Interfering, Signal Transduction, Starvation, Tumor Cells, Cultured, Tumor Suppressor Protein p53, Ubiquitin-Protein Ligases, X-Linked Inhibitor of Apoptosis Protein
EMBO J.
Date: Aug. 14, 2013
PubMed ID: 23749209
View in: Pubmed Google Scholar
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