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ERK와 JNK mitogen-activated protein kinase/Elk-1/Early growth response-1 경로를 통한 p53 비의존성 p21^(Waf1/Cip1) 유전자 전사조절

Title
ERK와 JNK mitogen-activated protein kinase/Elk-1/Early growth response-1 경로를 통한 p53 비의존성 p21^(Waf1/Cip1) 유전자 전사조절
Other Titles
Regulatory mechanism of p53-independent p12^(Waf1/Cip1) gene transcription through ERK and JNK mitogen-activated protein kinase/Elk-1/Early growth response-1 pathway
Author
최하영
Alternative Author(s)
Choi, Ha-Young
Advisor(s)
이영한
Issue Date
2007-02
Publisher
한양대학교
Degree
Master
Abstract
Cyclin-dependent kinase inhibitor p21^(Waf1/Cip1) 은 p53-의존적 그리고 p53-비의존적 기작에 의해 조절을 받는다. 정신병을 치료하는데 의학적으로 사용되는 phenothiazine derivative인 chlorpromazine (CPZ) 은 몇몇 암세포에서 세포 증식을 억제한다. 본 실험에서 rat C6 신경아교종 세포에 CPZ를 처리하였을 때 p53-비의존적으로 p21^(Waf1/Cip1) 의 유전자 전사가 활성화 되는 것을 확인하였다. Early growth response-1 (Egr-1) 은 많은 세포에서 세포의 분화와 성장, 세포사멸을 조절하는 전사 인자이다. CPZ에 의한 p21^(Waf1/Cip1) promoter 활성은 Egr-1의 일시적 발현에 의해 증가되나, egr-1 mRNA를 타겟으로 하는 small interference RNA (siRNA) 의 발현에 의해서는 증가하지 않았다. 그리고, CPZ 는 Mitogen-ativated protein (MAP) kinase 경로 중, p38을 통해서가 아닌, ERK1/2와 JNK1/2 경로를 통한 Ets-domain transcription factor Elk-1을 통하여 Egr-1의 발현을 촉진하였다. Egr-1 발현을 stable knockdown 시키자 CPZ에 의한 세포성장의 억제에 저항성이 나타났다. 본 실험을 통하여 C6 신경아교종 세포에서 CPZ 에 의한 p21^(Waf1/Cip1) 는 Egr-1에 매우 의존적이었다. 그리고 egr-1 유전자 발현에 있어서 ERK 와 JNK MAP kinase 경로를 통하여 Elk-1의 transactivation이 매개되고, p21^(Waf1/Cip1) 유전자의 전사가 조절된다.
The cyclin-dependent kinase inhibitor p21^(Waf1/Cip1) is regulated by both p53-dependent and p53-independent mechanisms. Chlorpromazine (CPZ), a phenothiazine derivative used clinically to control psychotic disorders, shows antiproliferative activity in some cancer cells. I show that p21^(Waf1/Cip1) gene transcription is activated independently of p53 by CPZ treatment in rat C6 glioma cells. Early growth response-1 (Egr-1) is a transcription factor that help regulates differentiation, growth, and apoptosis of many cell types. CPZ-induced p21^(Waf1/Cip1) promoter activity was enhanced by the transient expression of Egr-1, and suppressed by the function of small interference RNA (siRNA) targeted to egr-1 mRNA. In addition, CPZ stimulated egr-1 expression via Ets-domain transcription factor Elk-1 through the ERK1/2 and JNK1/2, but not the p38, mitogen-activated protein (MAP) kinase pathways. The stable knockdown of Egr-1 expression resulted in resistance to the CPZ-inducible inhibition of cell growth. I conclude that up-regulation of p21^(Waf1/Cip1) in response to CPZ treatment depends largely on Egr-1 in C6 glioma cells. My results establish a functional link between the ERK and JNK MAP kinase pathways that mediates the transactivation of Elk-1 and transcriptional control of the p21^(Waf1/Cip1) gene by a cascade that requires egr-1 gene expression.
URI
https://repository.hanyang.ac.kr/handle/20.500.11754/150114http://hanyang.dcollection.net/common/orgView/200000405375
Appears in Collections:
GRADUATE SCHOOL[S](대학원) > DEPARTMENT OF BIOCHEMISTRY(생화학과) > Theses (Master)
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