COX-2 regulates p53 activity and inhibits DNA damage-induced apoptosis.
We have previously shown that p53 induces cyclooxygenase-2 (COX-2) expression and COX-2 inhibits p53- or genotoxic stress-induced apoptosis. However, the COX-2 effects have been demonstrated indirectly by the use of a selective inhibitor, NS-398, and the molecular mechanisms by which COX-2 inhibits apoptosis have not been identified. In the present study, we demonstrated that COX-2 inhibits genotoxic stress-induced apoptosis by using an adenoviral COX-2 overexpression system. In addition, we found that COX-2 regulates the transcription function of p53 as evidenced by suppression of p53 target gene induction by COX-2 cotransfection. Furthermore, COX-2 interacted with p53 in vitro and in vivo, which was inhibited by the treatment with NS-398. Taken together, these results suggest a novel function of COX-2 that inhibits DNA damage-induced apoptosis through direct regulation of p53 function.
Choi
Eun-Mi
EM
Department of Biochemistry and Molecular Biology, Kangwon National University College of Medicine, Chuncheon 200-701, Republic of Korea.
Heo
Jee-In
JI
Oh
Jin-Young
JY
Kim
Young-Myeong
YM
Ha
Kwon-Soo
KS
Kim
Jong-Il
JI
Han
Jeong A
JA
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004249:DNA Damage / Q000187:drug effects / Q000502:physiology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008565:Membrane Proteins; D009578:Nitrobenzenes / Q000494:pharmacology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology*; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D008565:Membrane Proteins; D009578:Nitrobenzenes; D013449:Sulfonamides; D016159:Tumor Suppressor Protein p53; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases