An mTORC1-Mdm2-Drosha axis for miRNA biogenesis in response to glucose- and amino acid-deprivation

Peiying Ye; Yu Liu; Chong Chen; Fei Tang; Qi Wu; Xiang Wang; Chang-Gong Liu; Xiuping Liu; Runhua Liu; Yang Liu; Pan Zheng

doi:10.1016/j.molcel.2014.12.034

An mTORC1-Mdm2-Drosha axis for miRNA biogenesis in response to glucose- and amino acid-deprivation

Mol Cell. 2015 Feb 19;57(4):708-720. doi: 10.1016/j.molcel.2014.12.034. Epub 2015 Jan 29.

Authors

Peiying Ye¹, Yu Liu², Chong Chen², Fei Tang¹, Qi Wu³, Xiang Wang¹, Chang-Gong Liu⁴, Xiuping Liu⁴, Runhua Liu⁵, Yang Liu⁶, Pan Zheng⁷

Affiliations

¹ Center for Cancer and Immunology Research, Children's National Medical Center, Washington, DC 20010, USA.
² State Key Laboratory of Biotherapy, West China Center of Medical Sciences, Sichuan University, Chengdu, 610041 Sichuan, China.
³ Departments of Neurology, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.
⁴ Department of Experimental Therapeutics, MD Anderson Cancer Center, Houston, TX 77030, USA.
⁵ Department of Genetics, University of Alabama, Birmingham, Birmingham, AL 35294, USA.
⁶ Center for Cancer and Immunology Research, Children's National Medical Center, Washington, DC 20010, USA. Electronic address: [email protected].
⁷ Center for Cancer and Immunology Research, Children's National Medical Center, Washington, DC 20010, USA. Electronic address: [email protected].

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Amino Acids / metabolism
Animals
Gene Expression Regulation
Glucose / metabolism
HeLa Cells
Humans
Mechanistic Target of Rapamycin Complex 1
Mice, Inbred C57BL
MicroRNAs / biosynthesis*
Multiprotein Complexes / genetics
Multiprotein Complexes / metabolism
Multiprotein Complexes / physiology*
Proteolysis
Proto-Oncogene Proteins c-mdm2 / genetics
Proto-Oncogene Proteins c-mdm2 / metabolism
Proto-Oncogene Proteins c-mdm2 / physiology*
Ribonuclease III / genetics
Ribonuclease III / metabolism
Ribonuclease III / physiology*
TOR Serine-Threonine Kinases / genetics
TOR Serine-Threonine Kinases / metabolism
TOR Serine-Threonine Kinases / physiology*
Tumor Suppressor Protein p53 / physiology
Ubiquitination

Substances

Amino Acids
MicroRNAs
Multiprotein Complexes
Tumor Suppressor Protein p53
Mdm2 protein, mouse
Proto-Oncogene Proteins c-mdm2
Mechanistic Target of Rapamycin Complex 1
TOR Serine-Threonine Kinases
Drosha protein, mouse
Ribonuclease III
Glucose

Associated data

GEO/GSE64042
GEO/GSE64047
GEO/GSE64089

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding