title: Mg2+/Mn2+-dependent phosphatase 1A is involved in regulating pregnane X receptor-mediated cytochrome p450 3A4 gene expression.
abstract: Variations in the expression of human pregnane X receptor (hPXR)-mediated cytochrome p450 3A4 (CYP3A4) in liver can alter therapeutic response to a variety of drugs and may lead to potential adverse drug interactions. We sought to determine whether Mg(2+)/Mn(2+)-dependent phosphatase 1A (PPM1A) regulates hPXR-mediated CYP3A4 expression. PPM1A was found to be coimmunoprecipitated with hPXR. Genetic or pharmacologic activation of PPM1A led to a significant increase in hPXR transactivation of CYP3A4 promoter activity. In contrast, knockdown of endogenous PPM1A not only attenuated hPXR transactivation, but also increased proliferation of HepG2 human liver carcinoma cells, suggesting that PPM1A expression levels regulate hPXR, and that PPM1A expression is regulated in a proliferation-dependent manner. Indeed, PPM1A expression and hPXR transactivation were found to be significantly reduced in subconfluent HepG2 cells compared with confluent HepG2 cells, suggesting that both PPM1A expression and hPXR-mediated CYP3A4 expression may be downregulated in proliferating livers. Elevated PPM1A levels led to attenuation of hPXR inhibition by tumor necrosis factor-α and cyclin-dependent kinase-2, which are known to be upregulated and essential during liver regeneration. In mouse regenerating livers, similar to subconfluent HepG2 cells, expression of both PPM1A and the mouse PXR target gene cyp3a11 was found to be downregulated. Our results show that PPM1A can positively regulate PXR activity by counteracting PXR inhibitory signaling pathways that play a major role in liver regeneration. These results implicate a novel role for PPM1A in regulating hPXR-mediated CYP3A4 expression in hepatocytes and may explain a mechanism for CYP3A repression in regenerating livers.
authors.affiliation: Department of Anatomy, Physiology, and Pharmacology (S.R.P., P.C.F., K.L.A.) and Department of Nutrition, Dietetics, and Hospitality Management (J.R.B., S.D.R.), Auburn University, Auburn, Alabama; Department of Chemistry (T.G.), Auburn University at Montgomery, Montgomery, Alabama; Department of Chemical Biology and Therapeutics (T.C.), St. Jude Children's Research Hospital, Memphis, Tennessee; and Department of Pharmacology, Toxicology, and Therapeutics (U.A.), University of Kansas, Kansas City, Kansas srp0010@auburn.edu.
authors.forename: Satyanarayana R
authors.initials: SR
authors.lastname: Pondugula
authors.affiliation: Department of Anatomy, Physiology, and Pharmacology (S.R.P., P.C.F., K.L.A.) and Department of Nutrition, Dietetics, and Hospitality Management (J.R.B., S.D.R.), Auburn University, Auburn, Alabama; Department of Chemistry (T.G.), Auburn University at Montgomery, Montgomery, Alabama; Department of Chemical Biology and Therapeutics (T.C.), St. Jude Children's Research Hospital, Memphis, Tennessee; and Department of Pharmacology, Toxicology, and Therapeutics (U.A.), University of Kansas, Kansas City, Kansas.
authors.forename: Patrick C
authors.initials: PC
authors.lastname: Flannery
authors.affiliation: Department of Anatomy, Physiology, and Pharmacology (S.R.P., P.C.F., K.L.A.) and Department of Nutrition, Dietetics, and Hospitality Management (J.R.B., S.D.R.), Auburn University, Auburn, Alabama; Department of Chemistry (T.G.), Auburn University at Montgomery, Montgomery, Alabama; Department of Chemical Biology and Therapeutics (T.C.), St. Jude Children's Research Hospital, Memphis, Tennessee; and Department of Pharmacology, Toxicology, and Therapeutics (U.A.), University of Kansas, Kansas City, Kansas.
authors.forename: Udayan
authors.initials: U
authors.lastname: Apte
authors.affiliation: Department of Anatomy, Physiology, and Pharmacology (S.R.P., P.C.F., K.L.A.) and Department of Nutrition, Dietetics, and Hospitality Management (J.R.B., S.D.R.), Auburn University, Auburn, Alabama; Department of Chemistry (T.G.), Auburn University at Montgomery, Montgomery, Alabama; Department of Chemical Biology and Therapeutics (T.C.), St. Jude Children's Research Hospital, Memphis, Tennessee; and Department of Pharmacology, Toxicology, and Therapeutics (U.A.), University of Kansas, Kansas City, Kansas.
authors.forename: Jeganathan Ramesh
authors.initials: JR
authors.lastname: Babu
authors.affiliation: Department of Anatomy, Physiology, and Pharmacology (S.R.P., P.C.F., K.L.A.) and Department of Nutrition, Dietetics, and Hospitality Management (J.R.B., S.D.R.), Auburn University, Auburn, Alabama; Department of Chemistry (T.G.), Auburn University at Montgomery, Montgomery, Alabama; Department of Chemical Biology and Therapeutics (T.C.), St. Jude Children's Research Hospital, Memphis, Tennessee; and Department of Pharmacology, Toxicology, and Therapeutics (U.A.), University of Kansas, Kansas City, Kansas.
authors.forename: Thangiah
authors.initials: T
authors.lastname: Geetha
authors.affiliation: Department of Anatomy, Physiology, and Pharmacology (S.R.P., P.C.F., K.L.A.) and Department of Nutrition, Dietetics, and Hospitality Management (J.R.B., S.D.R.), Auburn University, Auburn, Alabama; Department of Chemistry (T.G.), Auburn University at Montgomery, Montgomery, Alabama; Department of Chemical Biology and Therapeutics (T.C.), St. Jude Children's Research Hospital, Memphis, Tennessee; and Department of Pharmacology, Toxicology, and Therapeutics (U.A.), University of Kansas, Kansas City, Kansas.
authors.forename: Shraddha D
authors.initials: SD
authors.lastname: Rege
authors.affiliation: Department of Anatomy, Physiology, and Pharmacology (S.R.P., P.C.F., K.L.A.) and Department of Nutrition, Dietetics, and Hospitality Management (J.R.B., S.D.R.), Auburn University, Auburn, Alabama; Department of Chemistry (T.G.), Auburn University at Montgomery, Montgomery, Alabama; Department of Chemical Biology and Therapeutics (T.C.), St. Jude Children's Research Hospital, Memphis, Tennessee; and Department of Pharmacology, Toxicology, and Therapeutics (U.A.), University of Kansas, Kansas City, Kansas.
authors.forename: Taosheng
authors.initials: T
authors.lastname: Chen
authors.affiliation: Department of Anatomy, Physiology, and Pharmacology (S.R.P., P.C.F., K.L.A.) and Department of Nutrition, Dietetics, and Hospitality Management (J.R.B., S.D.R.), Auburn University, Auburn, Alabama; Department of Chemistry (T.G.), Auburn University at Montgomery, Montgomery, Alabama; Department of Chemical Biology and Therapeutics (T.C.), St. Jude Children's Research Hospital, Memphis, Tennessee; and Department of Pharmacology, Toxicology, and Therapeutics (U.A.), University of Kansas, Kansas City, Kansas.
authors.forename: Kodye L
authors.initials: KL
authors.lastname: Abbott
mesh_terms: D000818:Animals; D019556:COS Cells; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D018844:Cyclin-Dependent Kinases / Q000235:genetics / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A / Q000235:genetics* / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics; D015870:Gene Expression / Q000235:genetics*; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010749:Phosphoprotein Phosphatases / Q000235:genetics / Q000378:metabolism*; D000077297:Pregnane X Receptor; D011401:Promoter Regions, Genetic / Q000235:genetics; D000071636:Protein Phosphatase 2C; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D015533:Transcriptional Activation / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics
chemical_list: D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D014409:Tumor Necrosis Factor-alpha; D051544:Cytochrome P-450 CYP3A; D018844:Cyclin-Dependent Kinases; C000607456:PPM1A protein, human; D010749:Phosphoprotein Phosphatases; C000607466:Ppm1a protein, mouse; D000071636:Protein Phosphatase 2C