Regulation of peroxisome proliferator-activated receptor α by protein kinase C

Joshua P. Gray, Katherine A. Burns, Tara L. Leas, Gary H. Perdew, John Patrick Vanden Heuvel

Research output: Contribution to journalArticle

34 Scopus citations

Abstract

Peroxisome proliferator-activated receptor α (PPARα) is a nuclear receptor activated by fatty acids, hypolipidemic drugs, and peroxisome proliferators (PPs). Like other nuclear receptors, PPARα is a phosphoprotein whose activity is affected by a variety of growth factor signaling cascades. In this study, the effects of protein kinase C (PKC) on PPARα activity were explored. In vivo phosphorylation studies in COS-1 cells transfected with murine PPARα showed that the level of phosphorylated PPARα is increased by treatment with the PP Wy-14,643 as well as the PKC activator phorbol myristol acetate (PMA). In addition, inhibitors of PKC decreased Wy-14,643-induced PPARα activity in a variety of reporter assays. Overexpressing PKCα, -β, -δ, and -ζ affected both basal and Wy-14,643-induced PPARα activity. Four consensus PKC phosphorylation sites are contained within the DNA binding (C-domain) and hinge (D-domain) regions of rat PPARα (S110, T129, S142, and S179), and their contribution to receptor function was examined. Mutation of T129 or S179 to alanine prevented heterodimerization of PPARα with RXRα, lowered the level of phosphorylation by PKCα and PKCδ in vitro, and lowered the level of phosphorylation of transfected PPARα in transfected cells. In addition, the T129A mutation prevented PPARα from binding DNA in an electromobility shift assay. Together, these studies demonstrate a direct role for PKC in the regulation of PPARα, and suggest several PKCs can regulate PPARα activity through multiple phosphorylation sites.

Original languageEnglish (US)
Pages (from-to)10313-10321
Number of pages9
JournalBiochemistry
Volume44
Issue number30
DOIs
StatePublished - Aug 2 2005

All Science Journal Classification (ASJC) codes

  • Biochemistry

Fingerprint Dive into the research topics of 'Regulation of peroxisome proliferator-activated receptor α by protein kinase C'. Together they form a unique fingerprint.

  • Cite this