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논문 기본 정보
- 자료유형
- 학술저널
- 저자정보
- 발행연도
- 2010.1
- 수록면
- 395 - 405 (11page)
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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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참고문헌 (25)
참고문헌 신청
Aicher WK / 1999 / Analysis of functional elements in the human Egr-1 gene promoter / Rheumatol Int 18 : 207 ~ 214
Baron V / 2003 / Antisense to the early growth response-1 gene (Egr-1) inhibits prostate tumor development in TRAMP mice / Ann NY Acad Sci 1002 : 197 ~ 216
Baron V / 2006 / The transcription factor Egr1 is a direct regulator of multiple tumor suppressors including TGFβ1, PTEN, p53 and fibronectin: Egr1 is a potential target of
Baus F / 2003 / Permanent cell cycle exit in G2 phase after DNA damage in normal human fibroblasts / EMBO J 22 : 3992 ~ 4002
Calogero A / 2004 / Inhibition of cell growth by EGR-1 in human primary cultures from malignant glioma / Cancer Cell Int 4 : 1 ~ 12
Baron V / 2003 / Antisense to the early growth response-1 gene (Egr-1) inhibits prostate tumor development in TRAMP mice / Ann NY Acad Sci 1002 : 197 ~ 216
Baron V / 2006 / The transcription factor Egr1 is a direct regulator of multiple tumor suppressors including TGFβ1, PTEN, p53 and fibronectin: Egr1 is a potential target of
Baus F / 2003 / Permanent cell cycle exit in G2 phase after DNA damage in normal human fibroblasts / EMBO J 22 : 3992 ~ 4002
Calogero A / 2004 / Inhibition of cell growth by EGR-1 in human primary cultures from malignant glioma / Cancer Cell Int 4 : 1 ~ 12
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