TY - JOUR
T1 - Autophagic and tumour suppressor activity of a novel Beclin1-binding protein UVRAG
AU - Liang, Chengyu
AU - Feng, Pinghui
AU - Ku, Bonsu
AU - Dotan, Iris
AU - Canaani, Dan
AU - Oh, Byung Ha
AU - Jung, Jae U.
N1 - Funding Information:
This work was partly supported by U.S. Public Health Service grants CA82057, CA91819, CA31363, CA106156, and RR00168 (JUJ), the Creative Research Initiative of Korea Ministry of Science and Technology (B.-H.O and B.-S.K.). P.F. is a Leukemia & Lymphoma Society Fellow. We thank B. Levine, M.J. Hardwick, S. Virgin, S. Field, N. Mizushima, T. Yoshimori, J. Backer and Y. Ohsumi for providing reagents, T. Seo and S. Dann for helping with the PI3KC3 assay, S. Gygi for mass spectrometry, J. Mackey for performing electron microscopy, and T.C. Taylor and K.G. Toney for helping with manuscript preparation. Finally, we thank all members of Tumor Virology Division for discussions.
PY - 2006/7
Y1 - 2006/7
N2 - Autophagy, the degradation of cytoplasmic components, is an evolutionarily conserved homeostatic process involved in environmental adaptation, lifespan determination and tumour development. The tumor suppressor Beclin1 is part of the PI(3) kinase class III (PI(3)KC3) lipid-kinase complex that induces autophagy. The autophagic activity of the Beclin1-PI(3)KC3 complex, however, is suppressed by Bcl-2. Here, we report the identification of a novel coiled-coil UV irradiation resistance-associated gene (UVRAG) as a positive regulator of the Beclin1-PI(3)KC3 complex. UVRAG, a tumour suppressor candidate that is monoallelically mutated at high frequency in human colon cancers, associates with the Beclin1-Bcl-2-PI(3)KC3 multiprotein complex, where UVRAG and Beclin1 interdependently induce autophagy. UVRAG-mediated activation of the Beclin1-PI(3)KC3 complex promotes autophagy and also suppresses the proliferation and tumorigenicity of human colon cancer cells. These results identify UVRAG as an essential component of the Beclin1-PI(3)KC3 lipid kinase complex that is an important signalling checkpoint for autophagy and tumour-cell growth.
AB - Autophagy, the degradation of cytoplasmic components, is an evolutionarily conserved homeostatic process involved in environmental adaptation, lifespan determination and tumour development. The tumor suppressor Beclin1 is part of the PI(3) kinase class III (PI(3)KC3) lipid-kinase complex that induces autophagy. The autophagic activity of the Beclin1-PI(3)KC3 complex, however, is suppressed by Bcl-2. Here, we report the identification of a novel coiled-coil UV irradiation resistance-associated gene (UVRAG) as a positive regulator of the Beclin1-PI(3)KC3 complex. UVRAG, a tumour suppressor candidate that is monoallelically mutated at high frequency in human colon cancers, associates with the Beclin1-Bcl-2-PI(3)KC3 multiprotein complex, where UVRAG and Beclin1 interdependently induce autophagy. UVRAG-mediated activation of the Beclin1-PI(3)KC3 complex promotes autophagy and also suppresses the proliferation and tumorigenicity of human colon cancer cells. These results identify UVRAG as an essential component of the Beclin1-PI(3)KC3 lipid kinase complex that is an important signalling checkpoint for autophagy and tumour-cell growth.
UR - http://www.scopus.com/inward/record.url?scp=33745751085&partnerID=8YFLogxK
U2 - 10.1038/ncb1426
DO - 10.1038/ncb1426
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C2 - 16799551
AN - SCOPUS:33745751085
SN - 1465-7392
VL - 8
SP - 688
EP - 698
JO - Nature Cell Biology
JF - Nature Cell Biology
IS - 7
ER -
