The Sam68 STAR RNA-binding protein regulates mTOR alternative splicing during adipogenesis

Mol Cell. 2012 Apr 27;46(2):187-99. doi: 10.1016/j.molcel.2012.02.007. Epub 2012 Mar 15.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics*
  • Adaptor Proteins, Signal Transducing / physiology
  • Adipogenesis / genetics*
  • Alternative Splicing*
  • Animals
  • Body Composition / genetics
  • Energy Metabolism / genetics
  • Mechanistic Target of Rapamycin Complex 1
  • Mice
  • Multiprotein Complexes
  • NIH 3T3 Cells
  • Phenotype
  • Proteins / metabolism
  • Proteins / physiology
  • RNA-Binding Proteins / genetics*
  • RNA-Binding Proteins / physiology
  • Signal Transduction / genetics
  • TOR Serine-Threonine Kinases / physiology*

Substances

  • Adaptor Proteins, Signal Transducing
  • Khdrbs1 protein, mouse
  • Multiprotein Complexes
  • Proteins
  • RNA-Binding Proteins
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • Mechanistic Target of Rapamycin Complex 1