Inactivation of wild-type p53 tumor suppressor by electrophilic prostaglandins
AUTOR(ES)
Moos, P. J.
FONTE
The National Academy of Sciences
RESUMO
The electrophilic eicosanoids prostaglandins A1 or A2 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 A1 and A2. Prostaglandins A1 and A2 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.
ACESSO AO ARTIGO
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=16848Documentos Relacionados
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