title: mTORC2 promotes cell survival through c-Myc-dependent up-regulation of E2F1.
abstract: Previous studies have reported that mTORC2 promotes cell survival through phosphorylating AKT and enhancing its activity. We reveal another mechanism by which mTORC2 controls apoptosis. Inactivation of mTORC2 promotes binding of CIP2A to PP2A, leading to reduced PP2A activity toward c-Myc serine 62 and, consequently, enhancement of c-Myc phosphorylation and expression. Increased c-Myc activity induces transcription of pri-miR-9-2/miR-9-3p, in turn inhibiting expression of E2F1, a transcriptional factor critical for cancer cell survival and tumor progression, resulting in enhanced apoptosis. In vivo experiments using B cell-specific mTORC2 (rapamycin-insensitive companion of mTOR) deletion mice and a xenograft tumor model confirmed that inactivation of mTORC2 causes up-regulation of c-Myc and miR-9-3p, down-regulation of E2F1, and consequent reduction in cell survival. Conversely, Antagomir-9-3p reversed mTORC1/2 inhibitor-potentiated E2F1 suppression and resultant apoptosis in xenograft tumors. Our in vitro and in vivo findings collectively demonstrate that mTORC2 promotes cell survival by stimulating E2F1 expression through a c-Myc- and miR-9-3p-dependent mechanism.
authors.affiliation: Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, China.
authors.forename: Zhipeng
authors.initials: Z
authors.lastname: Zou
authors.affiliation: Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, China.
authors.forename: Anling
authors.initials: A
authors.lastname: Liu
authors.affiliation: Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, China.
authors.forename: Xuan
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, China.
authors.forename: Qiancheng
authors.initials: Q
authors.lastname: Song
authors.affiliation: Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, China.
authors.forename: Chunhong
authors.initials: C
authors.lastname: Jia
authors.affiliation: Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, China.
authors.forename: Zhenguo
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Lin
authors.affiliation: Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, China.
authors.forename: Cuilan
authors.initials: C
authors.lastname: Yang
authors.affiliation: Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213.
authors.forename: Yu
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, China baixc15@smu.edu.cn.
authors.forename: Xiaochun
authors.initials: X
authors.lastname: Bai
mesh_terms: D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D001665:Binding Sites; D045744:Cell Line, Tumor; D002470:Cell Survival; D050687:E2F1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D057809:HEK293 Cells; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D000076225:Mechanistic Target of Rapamycin Complex 2; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000502:physiology; D046912:Multiprotein Complexes / Q000502:physiology*; D009368:Neoplasm Transplantation; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology*; D011687:Purines / Q000494:pharmacology; D034622:RNA Interference; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000502:physiology*; D015854:Up-Regulation
chemical_list: D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D007211:Indoles; C541874:MIRN92 microRNA, human; C489427:MYC protein, human; D035683:MicroRNAs; D046912:Multiprotein Complexes; D016271:Proto-Oncogene Proteins c-myc; D011687:Purines; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases; C572919:PP242; D020123:Sirolimus