Okadaic acid-induced transcriptional downregulation of type I collagen gene expression is mediated by protein phosphatase 2A.
Expression of type I collagen genes is highly regulated and becomes abnormal in various pathological conditions, from excessive collagen production in fibrotic diseases to their downregulation in transformed cells. Some inflammatory cytokines and other ligands, capable of eliciting intracellular phosphorylation, can profoundly alter collagen gene expression. We investigated the role of serine/threonine protein phosphatases (PP) in the regulation of collagen gene expression. Biosynthesis of the endogenous type I procollagen, and expression of Pro alpha 1(I) promoter-luciferase (Luc) constructs transfected in NIH3T3 fibroblasts, were evaluated in response to PP2A and PP1 inhibitor okadaic acid (OA) and exogenously expressed PP catalytic subunits. OA suppressed type I collagen gene expression as judged by reduced rates of protein synthesis, steady state levels of Pro alpha 1(I) collagen mRNA and expression of Luc driven by Pro alpha 1 (I) collagen promoter in OA-treated cells. Co-transfection of Pro alpha 1(I)-Luc with expression vectors containing PP2A, but not PP1, stimulated collagen promoter activity. These results strongly suggest that OA acts via PP2A-mediated dephosphorylation of an unidentified transcription factor(s) or cofactor(s) needed to activate Pro alpha 1(I) collagen promoter.
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Department of Pharmacology, College of Medicine, University of Tennessee, Memphis 38104, USA.
Raghow
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D016475:3T3 Cells; D000818:Animals; D015500:Chloramphenicol O-Acetyltransferase / Q000235:genetics / Q000378:metabolism; D003094:Collagen / Q000096:biosynthesis / Q000235:genetics*; D015536:Down-Regulation; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D051379:Mice; D019319:Okadaic Acid / Q000494:pharmacology*; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D011347:Procollagen / Q000096:biosynthesis / Q000235:genetics; D011401:Promoter Regions, Genetic; D054648:Protein Phosphatase 2; D012333:RNA, Messenger / Q000096:biosynthesis; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014158:Transcription, Genetic; D014162:Transfection
D011347:Procollagen; D012333:RNA, Messenger; D019319:Okadaic Acid; D003094:Collagen; D015500:Chloramphenicol O-Acetyltransferase; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2; D013755:Tetradecanoylphorbol Acetate