title: The Sam68 STAR RNA-binding protein regulates mTOR alternative splicing during adipogenesis.
abstract: We report that mice ablated for the Sam68 RNA-binding protein exhibit a lean phenotype as a result of increased energy expenditure, decreased commitment to early adipocyte progenitors, and defects in adipogenic differentiation. The Sam68(-/-) mice were protected from obesity, insulin resistance, and glucose intolerance induced with a high-fat diet. To identify the alternative splice events regulated by Sam68, genome-wide exon usage profiling in white adipose tissue was performed. Adipocytes from Sam68(-/-) mice retained intron 5 within the mTOR transcript introducing a premature termination codon, leading to an unstable mRNA. Consequently, Sam68-depleted cells had reduced mTOR levels resulting in lower levels of insulin-stimulated S6 and Akt phosphorylation leading to defects in adipogenesis, and this defect was rescued by the exogenous expression of full-length mTOR. Sam68 bound intronic splice elements within mTOR intron 5 required for the usage of the 5' splice site. We propose that Sam68 regulates alternative splicing during adipogenesis.
authors.affiliation: Terry Fox Molecular Oncology Group and Bloomfield Center for Research on Aging, Lady Davis Institute for Medical Research, McGill University, Montreal, QC H3T 1E2, Canada.
authors.forename: Marc-Étienne
authors.initials: MÉ
authors.lastname: Huot
authors.forename: Gillian
authors.initials: G
authors.lastname: Vogel
authors.forename: Amber
authors.initials: A
authors.lastname: Zabarauskas
authors.forename: Chau Tuan-Anh
authors.initials: CT
authors.lastname: Ngo
authors.forename: Jasmin
authors.initials: J
authors.lastname: Coulombe-Huntington
authors.forename: Jacek
authors.initials: J
authors.lastname: Majewski
authors.forename: Stéphane
authors.initials: S
authors.lastname: Richard
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000502:physiology; D050156:Adipogenesis / Q000235:genetics*; D017398:Alternative Splicing; D000818:Animals; D001823:Body Composition / Q000235:genetics; D004734:Energy Metabolism / Q000235:genetics; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes; D041681:NIH 3T3 Cells; D010641:Phenotype; D011506:Proteins / Q000378:metabolism / Q000502:physiology; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C513253:Khdrbs1 protein, mouse; D046912:Multiprotein Complexes; D011506:Proteins; D016601:RNA-Binding Proteins; C546843:mTOR protein, mouse; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases