Cyclic AMP-dependent protein kinase signaling modulates pregnane x receptor activity in a species-specific manner.
Pregnane x receptor is a ligand-activated transcription factor that regulates drug-inducible expression of several key cytochrome P450 enzymes and drug transporter proteins in liver and intestine in a species-specific manner. Activation of this receptor modulates several key biochemical pathways, including gluconeogenesis, beta-oxidation of fatty acids, fatty acid uptake, cholesterol homeostasis, and lipogenesis. It is of current interest to determine whether the interaction between pregnane x receptor and these key biochemical pathways is evolutionarily conserved. We show here that activation of the cyclic AMP-dependent protein kinase signaling pathway synergizes with pregnane x receptor-mediated gene activation in mouse hepatocytes. Conversely, cyclic AMP-dependent protein kinase signaling has a repressive effect upon pregnane x receptor-mediated gene activation in rat and human hepatocytes. We show that the human pregnane x receptor protein can serve as an effective substrate for catalytically active cyclic AMP-dependent protein kinase in vitro. Metabolic labeling of the protein in vivo indicates that human pregnane x receptor exists as a phosphoprotein and that activation of cyclic AMP-dependent protein kinase signaling modulates the phosphorylation status of pregnane x receptor. Activation of cyclic AMP-dependent protein kinase signaling also modulates the interactions of pregnane x receptor with protein cofactors. Our results define the species-specific impact of cyclic AMP-dependent protein kinase signaling on pregnane x receptor and provide a molecular explanation of cyclic AMP-dependent protein kinase-mediated repression of human pregnane x receptor activity. Taken together, our results identify a novel mode of regulation of pregnane x receptor activity and highlight prominent functional differences in the process across species.
Lichti-Kaiser
Kristin
K
Department of Pharmacology and Toxicology, University of Kansas, Lawrence, Kansas 66045, USA.
Xu
Chenshu
C
Staudinger
Jeff L
JL
D000818:Animals; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D004789:Enzyme Activation / Q000502:physiology; D006801:Humans; D008297:Male; D051379:Mice; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D000077297:Pregnane X Receptor; D051381:Rats; D011987:Receptors, Steroid / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013045:Species Specificity
D010750:Phosphoproteins; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D017868:Cyclic AMP-Dependent Protein Kinases