1. A genome-wide siRNA screen reveals multiple mTORC1 independent signaling pathways regulating autophagy under normal nutritional conditions
- Author
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Ramnik J. Xavier, Greg Hoffman, Junying Yuan, Bénédicte F. Py, Marta M. Lipinski, Wen Zhou, Jun Liu, John Blenis, Emily Hsu, Jason Eisenberg, Aylwin Ng, and Xuxin Liu
- Subjects
Programmed cell death ,MAP Kinase Signaling System ,mTORC1 ,Biology ,Mechanistic Target of Rapamycin Complex 1 ,BAG3 ,General Biochemistry, Genetics and Molecular Biology ,Article ,03 medical and health sciences ,Phosphatidylinositol 3-Kinases ,0302 clinical medicine ,Cell Line, Tumor ,Autophagy ,Humans ,RNA, Small Interfering ,Molecular Biology ,Transcription factor ,Protein kinase B ,030304 developmental biology ,Cell Proliferation ,0303 health sciences ,Cell growth ,TOR Serine-Threonine Kinases ,Proteins ,Cell Biology ,Cell biology ,SIGNALING ,Food ,030220 oncology & carcinogenesis ,Multiprotein Complexes ,CELLBIO ,Signal transduction ,Developmental Biology ,Genome-Wide Association Study ,Signal Transduction ,Transcription Factors - Abstract
SummaryAutophagy is a cellular catabolic mechanism that plays an essential function in protecting multicellular eukaryotes from neurodegeneration, cancer, and other diseases. However, we still know very little about mechanisms regulating autophagy under normal homeostatic conditions when nutrients are not limiting. In a genome-wide human siRNA screen, we demonstrate that under normal nutrient conditions upregulation of autophagy requires the type III PI3 kinase, but not inhibition of mTORC1, the essential negative regulator of starvation-induced autophagy. We show that a group of growth factors and cytokines inhibit the type III PI3 kinase through multiple pathways, including the MAPK-ERK1/2, Stat3, Akt/Foxo3, and CXCR4/GPCR, which are all known to positively regulate cell growth and proliferation. Our study suggests that the type III PI3 kinase integrates diverse signals to regulate cellular levels of autophagy, and that autophagy and cell proliferation may represent two alternative cell fates that are regulated in a mutually exclusive manner.
- Published
- 2009