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KMID : 0620920100420050395
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Experimental & Molecular Medicine
2010 Volume.42 No. 5 p.395 ~ p.405
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Chlorpromazine activates p21Waf1/Cip1 gene transcription via early growth response-1 (Egr-1) in C6 glioma cells
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Shin Soon-Young
Kim Chang-Gun
Kim Se-Hyun
Kim Yong-Sik
Lim Yoong-Ho
Lee Young-Han
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Abstract
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2-Chloro-10-[3(-dimethylamino)propyl]phenothiazinemonohydrochloride (chlorpromazine) is a phenothiazine derivative used clinically to control psychotic disorders. It also exhibits an anticancer activity. Treatment with chlorpromazine (CPZ) results in cell-cycle arrest at the G2/M phase in rat C6 glioma cells. CPZ reduces the expression of cell cycle-related proteins, such as cyclin D1, cyclin A, and cyclin B1, but causes an increase in the p21Waf1/Cip1 level. The molecular mechanism by which CPZ regulates p21Waf1/Cip1 expression is unknown. Here, we provide evidence that CPZ activates the p21Waf1/Cip1 gene promoter via induction of the transcription factor early growth response- 1 (Egr-1) independently of p53 in C6 cells. A point mutation in the Egr-1-binding motif within the p21Waf1/Cip1 promoter abrogated promoter inducibility due to CPZ. Forced expression of Egr-1 enhanced p21Waf1/Cip1 promoter activity. In contrast, knockdown of endogenous Egr-1 by small interference RNA attenuated CPZ-induced p21Waf1/Cip1 promoter activity. A chromatin immunoprecipitation assay demonstrated that Egr-1 binds to the p21Waf1/Cip1 gene promoter. Further analysis showed that the ERK and JNK MAP kinases are required for induction of Egr-1 by CPZ. Finally, stable silencing of Egr-1 expression lead to attenuated CPZ-inducible p21Waf1/Cip1 expression and inhibited G2/M phase cell-cycle arrest. These results demonstrate that a functional link between ERK and JNK MAP kinase pathways and p21Waf1/Cip1 induction via Egr-1 contributes to CPZ-induced anticancer activity in C6 glioma cells.
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KEYWORD
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chlorpromazine, c-Jun N-terminal kinase, cyclin-dependent kinase inhibitor p21, early growth response-1, extracellular signal-regulated kinase, tumor suppressor protein p53
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