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Induction of Early Growth Response-1 Gene Expression by Calmodulin Antagonist Trifluoperazine through the Activation of Elk-1 in Human Fibrosarcoma HT1080 Cells

Title
Induction of Early Growth Response-1 Gene Expression by Calmodulin Antagonist Trifluoperazine through the Activation of Elk-1 in Human Fibrosarcoma HT1080 Cells
Author
이영한
Issue Date
2001-03
Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
Citation
JOURNAL OF BIOLOGICAL CHEMISTRY, v. 276, issue. 11, page. 7797-7805
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-1gene 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 thatEgr-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-inducedEgr-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.
URI
https://www.sciencedirect.com/science/article/pii/S0021925819321180https://repository.hanyang.ac.kr/handle/20.500.11754/158598
ISSN
0021-9258
DOI
10.1074/jbc.M009465200
Appears in Collections:
COLLEGE OF SCIENCE AND CONVERGENCE TECHNOLOGY[E](과학기술융합대학) > ETC
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