期刊
CANCER BIOLOGY & THERAPY
卷 8, 期 6, 页码 555-563出版社
TAYLOR & FRANCIS INC
DOI: 10.4161/cbt.8.6.7742
关键词
MCF7; Wip1/PPM1D; p53; Bax; doxorubicin; apoptosis
类别
资金
- NCI [CA 79756]
The human breast cancer cell line MCF-7 carries an amplified PPM1D/Wip-1 gene and overexpresses Wip-1 phosphatase protein. MCF-7 cells also harbor a wild-type p53 gene. We established stable isogenic lines (MCF-Sp53 clones) which exhibit decreased levels of p53 protein. We show that although the PPM1 D gene is amplified in MCF-7 cells it is still expressed in a p53-dependent manner. Stable isogenic cell lines derived from MCF-7 cells (designated MCF-clones) were also established in which Wip-1 expression is significantly decreased by a plasmid-based PPM1D antisense RNA. Decreasing Wip-1 expression sensitized MCF-clones to doxorubicin-induced apoptosis. The enhanced apoptotic response was correlated with increased phosphorylation of N-terrminal p53-Ser15 and -Ser46 and increased expression of the pro-apoptotic Bax gene at both the mRNA and protein level. The enhanced apoptotic response was blocked by Bax-siRNA knock-down suggesting that the increased response was a result of increased Bax protein expression. Moreover, reporter gene assays using the Waf-1 and Bax promoters to drive a luciferase gene revealed that luciferase activity driven by the Bax promoter was enhanced in MCF-clones while luciferase activity driven by the Waf-1 promoter was decreased relative to parental MCF-7 cells. The study reveals a novel molecular mechanism involving Wip-1 phosphatase, p53 phosphorylation and an enhanced apoptotic response mediated by transcriptional activation of the pro-apoptotic Bax gene.
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