mTORC1 promotes cell growth via mA-dependent mRNA degradation.

TitlemTORC1 promotes cell growth via mA-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
Volume81
Issue10
Pagination2064-2075.e8
Date Published2021 05 20
ISSN1097-4164
KeywordsAdenosine, Animals, Base Sequence, Cell Cycle Proteins, Cell Line, Tumor, Cell Proliferation, Eukaryotic Initiation Factors, HEK293 Cells, Humans, Male, Mechanistic Target of Rapamycin Complex 1, Mice, Models, Biological, Protein Biosynthesis, Proto-Oncogene Proteins c-myc, Ribosomal Protein S6 Kinases, RNA Splicing Factors, RNA Stability, RNA, Messenger, Signal Transduction
Abstract

<p>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 N-methyladenosine (mA) RNA methyltransferase complex. This regulation is mediated by 5' UTR of WTAP mRNA that is targeted by eIF4A/4B. Single-nucleotide-resolution mA mapping revealed that MAX dimerization protein 2 (MXD2) mRNA contains mA, and increased mA 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 mA RNA modification and illuminates the WTAP-MXD2-cMyc axis as a potential therapeutic target for mTORC1-driven cancers.</p>

DOI10.1016/j.molcel.2021.03.010
Alternate JournalMol Cell
PubMed ID33756105
PubMed Central IDPMC8356906
Grant ListS10 OD023669 / OD / NIH HHS / United States
R01 HL121266 / HL / NHLBI NIH HHS / United States
DP1 DK113643 / DK / NIDDK NIH HHS / United States
T32 CA203702 / CA / NCI NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States
R01 GM051405 / GM / NIGMS NIH HHS / United States
F32 CA221104 / CA / NCI NIH HHS / United States
R35 NS111631 / NS / NINDS NIH HHS / United States
/ HHMI / Howard Hughes Medical Institute / United States
R01 CA186702 / CA / NCI NIH HHS / United States