title: XIAP inhibits autophagy via XIAP-Mdm2-p53 signalling.
abstract: 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.
authors.affiliation: Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, China.
authors.forename: Xing
authors.initials: X
authors.lastname: Huang
authors.forename: Zhengsheng
authors.initials: Z
authors.lastname: Wu
authors.forename: Yide
authors.initials: Y
authors.lastname: Mei
authors.forename: Mian
authors.initials: M
authors.lastname: Wu
mesh_terms: D000818:Animals; D001343:Autophagy / Q000502:physiology*; D015153:Blotting, Western; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D045325:HCT116 Cells; D057809:HEK293 Cells; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D051379:Mice; D008854:Microscopy, Electron; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology*; D013217:Starvation / Q000503:physiopathology; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism*
chemical_list: D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D051636:X-Linked Inhibitor of Apoptosis Protein; D051736:Proto-Oncogene Proteins c-mdm2; D044767:Ubiquitin-Protein Ligases