Protein kinase C alpha modulates liver X receptor alpha transactivation.
Liver X receptor alpha (LXRalpha), an oxysterol-activated nuclear hormone receptor, regulates the expression of genes involved in lipid and cholesterol homeostasis and inflammation. We show here that transactivation by LXRalpha in monkey kidney COS-1 (Cos-1) cells is decreased by activation of the protein kinase C (PKC) signaling pathway. In transient co-transfection assays, phorbol myristate acetate (PMA) suppressed LXR-dependent transactivation of LXR-responsive reporter genes or the natural promoter of the human ATP-binding cassette (ABC), ABCA1 gene. The decrease in LXR transactivation after PMA treatment was also observed in human embryonic kidney (HEK) 293 and human hepatocellular carcinoma (HepG2) cells. Moreover, endogenous LXR target genes, ABCA1 and sterol response element-binding protein-1c, were also decreased by PMA treatment in HEK293 cells as assessed by real-time PCR. The PMA-mediated decrease of LXR activity was blocked by the PKC inhibitor bisindolylmaleimide and mimicked by constitutively active PKCalpha. Nuclear extracts treated with PMA show no decrease in LXRalpha DNA binding as assessed by mobility shift and chromatin immunoprecipitation assays. Additionally, in vitro kinase assays demonstrate that PKCalpha can phosphorylate LXRalpha. Our findings reveal a mode of regulation of LXRalpha that may be relevant to disease conditions where aberrant PKC signaling is observed, such as diabetes.
Delvecchio
Christopher J
CJ
Department of Biochemistry and Biomedical Sciences, Faculty of Science McMaster University, 1280 Main Street West, BSB Room 101, L85 4KI, Hamilton, Ontario Canada.
Capone
John P
JP
D000818:Animals; D002460:Cell Line; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D010766:Phosphorylation; D051571:Protein Kinase C-alpha / Q000502:physiology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D047490:Retinoid X Receptor alpha / Q000378:metabolism; D015398:Signal Transduction; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D015533:Transcriptional Activation
D004268:DNA-Binding Proteins; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D047490:Retinoid X Receptor alpha; D004247:DNA; D051571:Protein Kinase C-alpha; D013755:Tetradecanoylphorbol Acetate