Reprogramming the posttranslational code of SRC-3 confers a switch in mammalian systems biology

Proc Natl Acad Sci U S A. 2010 Jun 15;107(24):11122-7. doi: 10.1073/pnas.1005262107. Epub 2010 Jun 1.

Abstract

Here we demonstrate that reprogramming steroid receptor coactivator-3 (SRC-3) function by changing its posttranslational modification (PTM) code drastically influences systems biology. These findings support the physiological importance of PTMs in directing in vivo functions of a master coregulator. We previously reported that the transactivation potential of SRC-3 is controlled in part by PTMs, although this data emanated from in vitro studies. To test the physiological implications of PTMs on SRC-3, we developed a knock-in mouse model containing mutations at four conserved phosphorylation sites. These mice displayed a systems biology phenotype with increased body weight and adiposity, coupled with reduced peripheral insulin sensitivity. Collectively, these phenotypes result from increased IGF1 signaling, due to elevated IGFBP3 levels. We provide convincing evidence that these mutations in SRC-3 promoted enhanced transcription of the IGFBP3 gene and globally influenced growth and metabolism. Consequently, these mice displayed increased liver tumorigenesis, which likely results from elevated IGF1 signaling.

Publication types

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

MeSH terms

  • Adiposity / genetics
  • Adiposity / physiology
  • Amino Acid Substitution
  • Animals
  • Binding Sites / genetics
  • Body Composition
  • Body Weight
  • Gene Knock-In Techniques
  • Humans
  • Insulin Resistance
  • Insulin-Like Growth Factor I / metabolism
  • Liver Neoplasms, Experimental / etiology
  • Liver Neoplasms, Experimental / genetics
  • Liver Neoplasms, Experimental / metabolism
  • Male
  • Mammals
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mutagenesis, Site-Directed
  • Nuclear Receptor Coactivator 3 / genetics*
  • Nuclear Receptor Coactivator 3 / metabolism*
  • Phenotype
  • Phosphorylation
  • Protein Processing, Post-Translational
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Signal Transduction
  • Systems Biology

Substances

  • Recombinant Proteins
  • insulin-like growth factor-1, mouse
  • Insulin-Like Growth Factor I
  • Ncoa3 protein, mouse
  • Nuclear Receptor Coactivator 3