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- W1963537728 abstract "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." @default.
- W1963537728 created "2016-06-24" @default.
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- W1963537728 date "2010-01-01" @default.
- W1963537728 modified "2023-10-11" @default.
- W1963537728 title "Chlorpromazine activates p21<sup>Waf1/Cip1</sup>gene transcription via early growth response-1 (Egr-1) in C6 glioma cells" @default.
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- W1963537728 doi "https://doi.org/10.3858/emm.2010.42.5.041" @default.
- W1963537728 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/2877254" @default.
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