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The prosurvival activity of p53 protects cells from UV-induced apoptosis by inhibiting c-Jun NH2-terminal kinase activity and mitochondrial death signaling.
- Source :
-
Cancer research [Cancer Res] 2004 Dec 01; Vol. 64 (23), pp. 8736-45. - Publication Year :
- 2004
-
Abstract
- 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.
- Subjects :
- Apoptosis physiology
Cell Growth Processes genetics
Cell Line, Tumor
DNA Repair genetics
Enzyme Activation
G1 Phase physiology
Gene Expression Regulation, Neoplastic physiology
Gene Expression Regulation, Neoplastic radiation effects
Humans
JNK Mitogen-Activated Protein Kinases metabolism
Lung Neoplasms genetics
Lung Neoplasms metabolism
Lung Neoplasms pathology
Mitochondria radiation effects
Signal Transduction physiology
Signal Transduction radiation effects
Transcriptional Activation
Transfection
Tumor Suppressor Protein p53 biosynthesis
Tumor Suppressor Protein p53 genetics
Tumor Suppressor Protein p53 metabolism
Ultraviolet Rays
Apoptosis radiation effects
JNK Mitogen-Activated Protein Kinases antagonists & inhibitors
Mitochondria physiology
Tumor Suppressor Protein p53 physiology
Subjects
Details
- Language :
- English
- ISSN :
- 0008-5472
- Volume :
- 64
- Issue :
- 23
- Database :
- MEDLINE
- Journal :
- Cancer research
- Publication Type :
- Academic Journal
- Accession number :
- 15574785
- Full Text :
- https://doi.org/10.1158/0008-5472.CAN-04-2584