title: An mTORC1-Mdm2-Drosha axis for miRNA biogenesis in response to glucose- and amino acid-deprivation.
abstract: mTOR senses nutrient and energy status to regulate cell survival and metabolism in response to environmental changes. Surprisingly, targeted mutation of Tsc1, a negative regulator of mTORC1, caused a broad reduction in miRNAs due to Drosha degradation. Conversely, targeted mutation of Raptor, an essential component of mTORC1, increased miRNA biogenesis. mTOR activation increased expression of Mdm2, which is hereby identified as the necessary and sufficient ubiquitin E3 ligase for Drosha. Drosha was induced by nutrient and energy deprivation and conferred resistance to glucose deprivation. Using a high-throughput screen of a miRNA library, we identified four miRNAs that were necessary and sufficient to protect cells against glucose-deprivation-induced apoptosis. These miRNA was regulated by glucose through the mTORC1-MDM2-DROSHA axis. Taken together, our data reveal an mTOR-Mdm2-Drosha pathway in mammalian cells that broadly regulates miRNA biogenesis as a response to alteration in cellular environment.
authors: Center for Cancer and Immunology Research, Children's National Medical Center, Washington, DC 20010, USA.
authors: Peiying
authors: P
authors: Ye
authors: State Key Laboratory of Biotherapy, West China Center of Medical Sciences, Sichuan University, Chengdu, 610041 Sichuan, China.
authors: Yu
authors: Y
authors: Liu
authors: State Key Laboratory of Biotherapy, West China Center of Medical Sciences, Sichuan University, Chengdu, 610041 Sichuan, China.
authors: Chong
authors: C
authors: Chen
authors: Center for Cancer and Immunology Research, Children's National Medical Center, Washington, DC 20010, USA.
authors: Fei
authors: F
authors: Tang
authors: Departments of Neurology, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.
authors: Qi
authors: Q
authors: Wu
authors: Center for Cancer and Immunology Research, Children's National Medical Center, Washington, DC 20010, USA.
authors: Xiang
authors: X
authors: Wang
authors: Department of Experimental Therapeutics, MD Anderson Cancer Center, Houston, TX 77030, USA.
authors: Chang-Gong
authors: CG
authors: Liu
authors: Department of Experimental Therapeutics, MD Anderson Cancer Center, Houston, TX 77030, USA.
authors: Xiuping
authors: X
authors: Liu
authors: Department of Genetics, University of Alabama, Birmingham, Birmingham, AL 35294, USA.
authors: Runhua
authors: R
authors: Liu
authors: Center for Cancer and Immunology Research, Children's National Medical Center, Washington, DC 20010, USA. Electronic address: yaliu@cnmc.org.
authors: Yang
authors: Y
authors: Liu
authors: Center for Cancer and Immunology Research, Children's National Medical Center, Washington, DC 20010, USA. Electronic address: pzheng@cnmc.org.
authors: Pan
authors: P
authors: Zheng
mesh_terms: D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000096:biosynthesis*; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D059748:Proteolysis; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D043244:Ribonuclease III / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology; D054875:Ubiquitination
chemical_list: D000596:Amino Acids; D035683:MicroRNAs; D046912:Multiprotein Complexes; D016159:Tumor Suppressor Protein p53; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; C513400:Drosha protein, mouse; D043244:Ribonuclease III; D005947:Glucose
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