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mTORC1 promotes cell growth via m6A-dependent mRNA degradation.
Cho, Sungyun; Lee, Gina; Pickering, Brian F; Jang, Cholsoon; Park, Jin H; He, Long; Mathur, Lavina; Kim, Seung-Soo; Jung, Sunhee; Tang, Hong-Wen; Monette, Sebastien; Rabinowitz, Joshua D; Perrimon, Norbert; Jaffrey, Samie R; Blenis, John.
Afiliação
  • Cho S; Department of Pharmacology, Meyer Cancer Center, Weill Cornell Medicine, Cornell University, New York, NY, USA.
  • Lee G; 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
  • Pickering BF; Department of Pharmacology, Meyer Cancer Center, Weill Cornell Medicine, Cornell University, New York, NY, USA.
  • Jang C; 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.
  • Park JH; Department of Pharmacology, Meyer Cancer Center, Weill Cornell Medicine, Cornell University, New York, NY, USA.
  • He L; Department of Pharmacology, Meyer Cancer Center, Weill Cornell Medicine, Cornell University, New York, NY, USA.
  • Mathur L; Department of Microbiology and Molecular Genetics, Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine, Irvine, CA, USA.
  • Kim SS; Department of Obstetrics and Gynecology, Irving Medical Center, Columbia University, New York, NY, USA.
  • Jung S; Department of Biological Chemistry, Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine, Irvine, CA, USA.
  • Tang HW; Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, USA; Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore.
  • Monette S; Laboratory of Comparative Pathology, Memorial Sloan Kettering Cancer Center, The Rockefeller University, Weill Cornell Medicine, New York, NY, USA.
  • Rabinowitz JD; Department of Chemistry, Lewis Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA.
  • Perrimon N; Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, USA; Howard Hughes Medical Institute, Boston, MA, USA.
  • Jaffrey SR; Department of Pharmacology, Meyer Cancer Center, Weill Cornell Medicine, Cornell University, New York, NY, USA. Electronic address: srj2003@med.cornell.edu.
  • Blenis J; Department of Pharmacology, Meyer Cancer Center, Weill Cornell Medicine, Cornell University, New York, NY, USA. Electronic address: job2064@med.cornell.edu.
Mol Cell ; 81(10): 2064-2075.e8, 2021 05 20.
Article em En | MEDLINE | ID: mdl-33756105
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.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Adenosina / Estabilidade de RNA / Alvo Mecanístico do Complexo 1 de Rapamicina Tipo de estudo: Prognostic_studies Limite: Animals / Humans / Male Idioma: En Ano de publicação: 2021 Tipo de documento: Article
Texto completo
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Adenosina / Estabilidade de RNA / Alvo Mecanístico do Complexo 1 de Rapamicina Tipo de estudo: Prognostic_studies Limite: Animals / Humans / Male Idioma: En Ano de publicação: 2021 Tipo de documento: Article