Sterol Regulatory Element-Binding Protein 1 Is Negatively Modulated by PKA Phosphorylation

Am J Physiol Cell Physiol. 2006 Jun;290(6):C1477-86. doi: 10.1152/ajpcell.00374.2005. Epub 2005 Dec 28.

Abstract

Sterol regulatory element-binding protein (SREBP)-1a and -1c are key transcription factors that regulate lipid biosynthesis in cells. We identified that Ser338 located at the NH2 terminus of SREBP-1a is a PKA phosphorylation site in vitro and in HepG2 cells. PKA phosphorylation of this site attenuated DNA occupancy, as revealed by chromatin immunoprecipitation assay, and the ensuing transactivation. In contrast, replacing Ser with Ala [SREBP-1a(N)-S338A] increased transactivation. Although it forms heterodimers with the wild-type SREBP-1a(N) or S338A but not a homodimer with itself, SREBP-1a(N)-S338D (replacing Ser with Asp) decreased DNA binding. Ser314 of SREBP-1c, the counterpart of SREBP-1a Ser338, was also phosphorylated by PKA. Accordingly, the adenovirus-mediated expression of SREBP-1c(N)-S314D in HepG2 cells retarded lipogenesis. Our results indicate that the cAMP-PKA pathway, by phosphorylating SREBP-1, may modulate lipid metabolism in liver cell lines.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Blotting, Western
  • Cell Line, Tumor
  • Cyclic AMP / metabolism
  • Cyclic AMP-Dependent Protein Kinases
  • Electrophoretic Mobility Shift Assay
  • Humans
  • Lipid Metabolism / genetics*
  • Molecular Sequence Data
  • Phosphorylation
  • Polymerase Chain Reaction
  • Protein Processing, Post-Translational
  • Protein Transport / physiology
  • Protein-Serine-Threonine Kinases / metabolism*
  • Sequence Homology, Amino Acid
  • Sterol Regulatory Element Binding Protein 1 / genetics
  • Sterol Regulatory Element Binding Protein 1 / metabolism*
  • Transcriptional Activation
  • Transfection

Substances

  • Sterol Regulatory Element Binding Protein 1
  • Cyclic AMP
  • Protein-Serine-Threonine Kinases
  • Cyclic AMP-Dependent Protein Kinases