mTORC1 promotes cell growth via m6A-dependent mRNA degradation

Sungyun Cho; Gina Lee; Brian F Pickering; Cholsoon Jang; Jin H Park; Long He; Lavina Mathur; Seung-Soo Kim; Sunhee Jung; Hong-Wen Tang; Sebastien Monette; Joshua D Rabinowitz; Norbert Perrimon; Samie R Jaffrey; John Blenis

doi:10.1016/j.molcel.2021.03.010

mTORC1 promotes cell growth via m⁶A-dependent mRNA degradation

Mol Cell. 2021 May 20;81(10):2064-2075.e8. doi: 10.1016/j.molcel.2021.03.010. Epub 2021 Mar 22.

Authors

Sungyun Cho¹, Gina Lee², Brian F Pickering¹, Cholsoon Jang³, Jin H Park¹, Long He¹, Lavina Mathur⁴, Seung-Soo Kim⁵, Sunhee Jung⁶, Hong-Wen Tang⁷, Sebastien Monette⁸, Joshua D Rabinowitz⁹, Norbert Perrimon¹⁰, Samie R Jaffrey¹¹, John Blenis¹²

Affiliations

¹ Department of Pharmacology, Meyer Cancer Center, Weill Cornell Medicine, Cornell University, New York, NY, USA.
² Department of Pharmacology, Meyer Cancer Center, Weill Cornell Medicine, Cornell University, New York, NY, USA; Department of Microbiology and Molecular Genetics, Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine, Irvine, CA, USA. Electronic address: ginalee@uci.edu.
³ Department of Chemistry, Lewis Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA; Department of Biological Chemistry, Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine, Irvine, CA, USA.
⁴ Department of Microbiology and Molecular Genetics, Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine, Irvine, CA, USA.
⁵ Department of Obstetrics and Gynecology, Irving Medical Center, Columbia University, New York, NY, USA.
⁶ Department of Biological Chemistry, Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine, Irvine, CA, USA.
⁷ Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, USA; Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore.
⁸ Laboratory of Comparative Pathology, Memorial Sloan Kettering Cancer Center, The Rockefeller University, Weill Cornell Medicine, New York, NY, USA.
⁹ Department of Chemistry, Lewis Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA.
¹⁰ Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, USA; Howard Hughes Medical Institute, Boston, MA, USA.
¹¹ Department of Pharmacology, Meyer Cancer Center, Weill Cornell Medicine, Cornell University, New York, NY, USA. Electronic address: srj2003@med.cornell.edu.
¹² Department of Pharmacology, Meyer Cancer Center, Weill Cornell Medicine, Cornell University, New York, NY, USA. Electronic address: job2064@med.cornell.edu.

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.

Keywords: MXD2; Protein translation; S6K1; WTAP; YTHDF readers; cMyc; eIF4A; m(6)A mRNA modification; mRNA stability; mTORC1.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adenosine / analogs & derivatives*
Adenosine / metabolism
Animals
Base Sequence
Cell Cycle Proteins / metabolism
Cell Line, Tumor
Cell Proliferation
Eukaryotic Initiation Factors / metabolism
HEK293 Cells
Humans
Male
Mechanistic Target of Rapamycin Complex 1 / metabolism*
Mice
Models, Biological
Protein Biosynthesis
Proto-Oncogene Proteins c-myc / metabolism
RNA Splicing Factors / metabolism
RNA Stability*
RNA, Messenger / genetics
RNA, Messenger / metabolism
Ribosomal Protein S6 Kinases / metabolism
Signal Transduction

Substances

Cell Cycle Proteins
Eukaryotic Initiation Factors
Proto-Oncogene Proteins c-myc
RNA Splicing Factors
RNA, Messenger
WTAP protein, human
eIF-4B
N-methyladenosine
Mechanistic Target of Rapamycin Complex 1
Ribosomal Protein S6 Kinases
Adenosine

Abstract

Publication types

MeSH terms

Substances

Grants and funding