The prosurvival activity of p53 protects cells from UV-induced apoptosis by inhibiting c-Jun NH2-terminal kinase activity and mitochondrial death signaling.
The cytoprotective function of p53 recently has been exploited as a therapeutic advantage for cancer prevention; agents activating the prosurvival activity of p53 are shown to prevent UV-induced damages. To explore the mechanisms of p53-mediated protection from UV-induced apoptosis, we have established stable clones of H1299 lung carcinoma cells expressing a temperature-sensitive p53 mutant, tsp53(V143A). At the permissive temperature of 32 degrees C, the tsp53(V143A)-expressing cells were arrested in G(1) phase without the occurrence of apoptosis; consistent with this is the preferential induction of genes related to growth arrest and DNA damage repair. Previous expression of functional tsp53(V143A) for > or =18 hours inhibited the release of proapoptotic molecules from mitochondria and protected the cells from UV-induced apoptosis; moreover, it suppressed the activation of c-Jun NH(2)-terminal kinase (JNK) signaling and relieved the effect of UV on p53 target gene activation. p53 associated with JNK and inhibited its kinase activity. Using the p53-null H1299 cells, we showed that inhibition of JNK blocked the UV-elicited mitochondrial death signaling and caspase activation. Our results suggest that the ability of p53 to bind and inactivate JNK, together with the activation of the p53 target genes related to cell cycle arrest and DNA damage repair, is responsible for its protection of cells against UV-induced apoptosis.
Lo
Pang-Kuo
PK
Institute of Biochemistry, National Yang-Ming University, Shih-Pai, Taipei, Taiwan.
Huang
Sheng-Zhu
SZ
Chen
Hsiang-Chin
HC
Wang
Fung-Fang
FF
D017209:Apoptosis / Q000502:physiology / Q000528:radiation effects*; D048708:Cell Growth Processes / Q000235:genetics; D045744:Cell Line, Tumor; D004260:DNA Repair / Q000235:genetics; D004789:Enzyme Activation; D016193:G1 Phase / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology / Q000528:radiation effects; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008928:Mitochondria / Q000502:physiology* / Q000528:radiation effects; D015398:Signal Transduction / Q000502:physiology / Q000528:radiation effects; D015533:Transcriptional Activation; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014466:Ultraviolet Rays
D016159:Tumor Suppressor Protein p53; D048031:JNK Mitogen-Activated Protein Kinases