mTORC1 promotes cell growth via m 6 A-dependent mRNA degradation.

TitlemTORC1 promotes cell growth via m 6 A-dependent mRNA degradation.
Publication TypeJournal Article
Year of Publication2021
AuthorsCho, S, Lee, G, Pickering, BF, Jang, C, Park, JH, He, L, Mathur, L, Kim, S-S, Jung, S, Tang, H-W, Monette, S, Rabinowitz, JD, Perrimon, N, Jaffrey, SR, Blenis, J
JournalMol Cell
Date Published2021 Mar 19

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.

Alternate JournalMol Cell
PubMed ID33756105
Grant ListP30 CA008748 / CA / NCI NIH HHS / United States
R35 NS111631 / NS / NINDS NIH HHS / United States