mTORC1 promotes cell growth via m(6)A-dependent mRNA degradation Journal Article

Authors: Cho, S.; Lee, G.; Pickering, B. F.; Jang, C.; Park, J. H.; He, L.; Mathur, L.; Kim, S. S.; Jung, S.; Tang, H. W.; Monette, S.; Rabinowitz, J. D.; Perrimon, N.; Jaffrey, S. R.; Blenis, J.
Article Title: mTORC1 promotes cell growth via m(6)A-dependent mRNA degradation
Abstract: Dysregulated mTORC1 signaling alters a wide range of cellular processes, contributing to metabolic disorders and cancer. Defining the molecular details of downstream effectors is thus critical for uncovering selective therapeutic targets. We report that mTORC1 and its downstream kinase S6K enhance eIF4A/4B-mediated translation of Wilms’ tumor 1-associated protein (WTAP), an adaptor for the N6-methyladenosine (m6A) RNA methyltransferase complex. This regulation is mediated by 5′ UTR of WTAP mRNA that is targeted by eIF4A/4B. Single-nucleotide-resolution m6A mapping revealed that MAX dimerization protein 2 (MXD2) mRNA contains m6A, and increased m6A modification enhances its degradation. WTAP induces cMyc-MAX association by suppressing MXD2 expression, which promotes cMyc transcriptional activity and proliferation of mTORC1-activated cancer cells. These results elucidate a mechanism whereby mTORC1 stimulates oncogenic signaling via m6A RNA modification and illuminates the WTAP-MXD2-cMyc axis as a potential therapeutic target for mTORC1-driven cancers. © 2021 Elsevier Inc.
Keywords: protein translation; mtorc1; mrna stability; eif4a; cmyc; m6a mrna modification; mxd2; s6k1; wtap; ythdf readers
Journal Title: Molecular Cell
Volume: 81
Issue: 10
ISSN: 1097-2765
Publisher: Cell Press  
Date Published: 2021-05-20
Start Page: 2064
End Page: 2075.e8
Language: English
DOI: 10.1016/j.molcel.2021.03.010
PUBMED: 33756105
PROVIDER: scopus
PMCID: PMC8356906
Notes: Article -- Export Date: 1 June 2021 -- Source: Scopus
Citation Impact
MSK Authors
  1. Sebastien Monette
    108 Monette