期刊
CELL CYCLE
卷 4, 期 9, 页码 1247-1253出版社
LANDES BIOSCIENCE
DOI: 10.4161/cc.4.9.1966
关键词
NF-kappa B; GADD45 family; p53; serine 15; phosphorylation; JNK; apoptosis
类别
资金
- NCI NIH HHS [1R01 CA85467, P50 CA090381, P50 CA105009] Funding Source: Medline
The p53 tumor suppressor gene plays an important role during induction of apoptosis in cancer. In contrast, NF-kappa B prevents apoptosis in response to chemotherapeutic agents and is a critical regulator of cell survival. Despite the riches of information on the regulation of wild-type p53 function by phosphorylation, nothing is known about the modulation of mutant p53 activity by phosphorylation. Here we report that inhibition of NF-kappa B in DU145 prostate cancer cells results in p53 mutant phosphorylation at serine 15 (Ser15), leading to an increase of p53 stability, DNA binding and gain of function. Serine 15-phosphorylation is due to GADD45 alpha-dependent induction of JNK kinase, which can be blocked by SP600125, a JNK kinase inhibitor. Furthermore, inhibition of GADD45 alpha by small interfering RNA blocks JNK activation and abrogates Ser15 phosphorylation. Together, these results highlight the importance of Ser15 phosphorylation in regulating the oncogenic function of mutant p53 and apoptosis induction in the context of the NF-kappa B/I kappa B signaling pathway.
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