mTORC1 promotes cell growth via mA-dependent mRNA degradation. Author Sungyun Cho, Gina Lee, Brian Pickering, Cholsoon Jang, Jin Park, Long He, Lavina Mathur, Seung-Soo Kim, Sunhee Jung, Hong-Wen Tang, Sebastien Monette, Joshua Rabinowitz, Norbert Perrimon, Samie Jaffrey, John Blenis Publication Year 2021 Type Journal Article 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 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. Keywords Animals, Protein Biosynthesis, Mice, Base Sequence, RNA, Messenger, Humans, Models, Biological, Signal Transduction, Cell Proliferation, Male, HEK293 Cells, Cell Cycle Proteins, Cell Line, Tumor, RNA Stability, Mechanistic Target of Rapamycin Complex 1, Adenosine, Eukaryotic Initiation Factors, Proto-Oncogene Proteins c-myc, RNA Splicing Factors, Ribosomal Protein S6 Kinases Journal Mol Cell Volume 81 Issue 10 Pages 2064-2075.e8 Date Published 2021 May 20 ISSN Number 1097-4164 DOI 10.1016/j.molcel.2021.03.010 Alternate Journal Mol Cell PMCID PMC8356906 PMID 33756105 PubMedPubMed CentralGoogle ScholarBibTeXEndNote X3 XML