Cyclooxygenase-2 interacts with p53 and interferes with p53-dependent transcription and apoptosis.
Cyclooxygenase-2 (COX-2) has been implicated in a variety of human malignancies and, accordingly, COX-2 selective inhibitors are being investigated as important chemopreventive and therapeutic agents. How COX-2 overexpression results in tumorigenesis and how COX-2 selective agents mediate their chemopreventive effects are issues that remain poorly understood. Here we report that the tumor suppressor p53 upregulates COX-2 expression and that COX-2 can in turn inhibit p53-dependent transcription. Additionally, a COX-2-selective inhibitor potentiates p53-induced apoptosis, which also supports the notion that COX-2 activity appears to interfere with p53 function. Expression of exogenous COX-2 in p53 wild-type cells does not affect the cytoplasmic or nuclear levels of p53, suggesting that COX-2 may not affect p53 turnover or subcellular localization. We further demonstrate that endogenous COX-2 interacts with p53 and that COX-2 and p53 interactions are a physiologically relevant event. Thus, p53 upregulates COX-2 and COX-2 in turn appears to negatively affect p53 activity via mechanisms that could involve physical interactions between COX-2 and p53. Based on our results, we propose that p53-dependent upregulation and activation of COX-2 appear to be yet another novel mechanism by which p53 could abate its own growth-inhibitory and apoptotic effects.
Corcoran
Chad A
CA
Department of Pharmacology, State University of New York, Upstate Medical University, Syracuse, NY 13210, USA.
He
Qin
Q
Huang
Ying
Y
Sheikh
M Saeed
MS
D017209:Apoptosis / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2; D005260:Female; D016158:Genes, p53; D006801:Humans; D008297:Male; D008565:Membrane Proteins; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology; D014158:Transcription, Genetic / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D008565:Membrane Proteins; D016159:Tumor Suppressor Protein p53; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases