title: Inactivation of wild-type p53 tumor suppressor by electrophilic prostaglandins.
abstract: The electrophilic eicosanoids prostaglandins A(1) or A(2) impaired p53-dependent transcription of endogenous genes and exogenous p53-luciferase reporter plasmids in RKO and HCT 116 colon cancer cells. Cellular accumulation of genetically wild-type, but transcriptionally silent p53 varied as a function of exposure time and concentration of prostaglandins A(1) and A(2). Prostaglandins A(1) and A(2) induced a conformational change in wild-type p53 that corresponded with its inactivation and its aberrant redistribution from the cytosol to the nucleus. Derangement of its transcriptional activity manifested as inhibition of p53-mediated apoptosis by etoposide, a representative antineoplastic agent. We conclude that electrophilic eicosanoids impair the role of wild-type p53 as a guardian of genomic integrity by a process distinct from somatic mutation or viral oncoprotein binding. This process may pertain to malignant and premalignant conditions, such as colon carcinoma and adenoma, which often harbor a genetically wild-type, but inactive form of p53 tumor suppressor.
authors.affiliation: Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope, Salt Lake City, UT 84112-5550, USA.
authors.forename: P J
authors.initials: PJ
authors.lastname: Moos
authors.forename: K
authors.initials: K
authors.lastname: Edes
authors.forename: F A
authors.initials: FA
authors.lastname: Fitzpatrick
mesh_terms: D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics; D005786:Gene Expression Regulation; D016158:Genes, p53; D006801:Humans; D011454:Prostaglandins A / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D011454:Prostaglandins A; D012333:RNA, Messenger