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Title 

Induction of early growth response-1 gene expression by calmodulin antagonist trifluoperazine through the activation of Elk-1 in human fibrosarcoma HT1080 cells

Authors 

Soon Young ShinSeong Yong KimJung Hye KimDo Sik MinJe Sang KoUng Gu KangYong Sik KimTaeg Kyu KwonMi Young HanYoung Ho KimYoung Han Lee

Publisher 

American Society for Biochemistry and Molecular Biology

Issue Date 

2001

Citation 

Journal of Biological Chemistry, vol. 276, no. 11, pp. 7797-7805

Keywords 

cell culturegenesgrowth kineticshuman promotersgenetic engineering1 [n,o bis(5 isoquinolinesulfonyl) n methyltyrosyl] 4 phenylpiperazinecalmodulinearly growth response factor 1protein kinase (calcium,calmodulin) IItrifluoperazine

Abstract 

The early growth response gene-1 (Egr-1) is a transcription factor that plays an important role in cell growth and differentiation. It has been known that Egr-1 expression is down-regulated in many types of tumor tissues, including human fibrosarcoma HT1080 cells, and introduction of the Egr-1 gene into HT1080 cells inhibits cell growth and tumorigenic potential. Trifluoperazine (TFP), a phenothiazine class calmodulin antagonist, is known to inhibit DNA synthesis and cell proliferation and potentially important in antitumor activities. To understand the regulatory mechanism of Egr-1, we investigated the effect of TFP on expression of Egr-1 in HT1080 cells. Herein, we report that Egr-1 expression was increased by TFP in synergy with serum at the transcriptional level. Both the Ca2+/calmodulin-dependent protein kinase II inhibitor KN62 and the calcineurin inhibitor cyclosporin A enhanced TFP-dependent increase of Egr-1, suggesting that the Ca2+/ calmodulindependent pathway plays a role in regulation of Egr-1 expression in HT1080 cells. The TFP-stimulated increase of the Egr-1 protein was preferentially inhibited by the MEK-specific inhibitor PD98059. In addition, activation of human Egr-1 promoter and the transcriptional activation of the ternary complex factor Elk-1 induced by TFP were inhibited both by pretreatment of PD98059 and by expression of the dominant-negative RasN17. These results indicate that the Ras/MEK/Erk/Elk-1 pathway is necessary for TFP-induced Egr-1 expression. We propose that the calmodulin antagonist TFP stimulates Egr-1 gene expression by modulating Ras/MEK/Erk and activation of the Elk-1 pathway in human fibrosarcoma HT1080 cells.

ISSN 

0021-9258

Link 

http://dx.doi.org/10.1074/jbc.M009465200 PubMed ID: 11121417

Appears in Collections

1. Journal Articles > Journal Articles

Registered Date

2017-04-19


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