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

Soon Young Shin, Seong Yong Kim, Jung Hye Kim, Do Sik Min, Jesang Ko, Ung Gu Kang, Yong Sik Kim, Taeg Kyu Kwon, Mi Young Han, Young Ho Kim, Young Han Lee

Research output: Contribution to journalArticle

33 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)7797-7805
Number of pages9
JournalJournal of Biological Chemistry
Volume276
Issue number11
DOIs
Publication statusPublished - 2001 Mar 16

Fingerprint

Trifluoperazine
Fibrosarcoma
Calmodulin
Gene expression
Genes
Chemical activation
Gene Expression
Growth
Mitogen-Activated Protein Kinase Kinases
Cell growth
Ternary Complex Factors
Calcium-Calmodulin-Dependent Protein Kinase Type 2
Cell proliferation
Protein Kinase Inhibitors
Cyclosporine
Tumors
Transcriptional Activation

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Shin, Soon Young ; Kim, Seong Yong ; Kim, Jung Hye ; Min, Do Sik ; Ko, Jesang ; Kang, Ung Gu ; Kim, Yong Sik ; Kwon, Taeg Kyu ; Han, Mi Young ; Kim, Young Ho ; Lee, Young Han. / Induction of Early Growth Response-1 Gene Expression by Calmodulin Antagonist Trifluoperazine through the Activation of Elk-1 in Human Fibrosarcoma HT1080 Cells. In: Journal of Biological Chemistry. 2001 ; Vol. 276, No. 11. pp. 7797-7805.
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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.",
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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. / Shin, Soon Young; Kim, Seong Yong; Kim, Jung Hye; Min, Do Sik; Ko, Jesang; Kang, Ung Gu; Kim, Yong Sik; Kwon, Taeg Kyu; Han, Mi Young; Kim, Young Ho; Lee, Young Han.

In: Journal of Biological Chemistry, Vol. 276, No. 11, 16.03.2001, p. 7797-7805.

Research output: Contribution to journalArticle

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T1 - Induction of Early Growth Response-1 Gene Expression by Calmodulin Antagonist Trifluoperazine through the Activation of Elk-1 in Human Fibrosarcoma HT1080 Cells

AU - Shin, Soon Young

AU - Kim, Seong Yong

AU - Kim, Jung Hye

AU - Min, Do Sik

AU - Ko, Jesang

AU - Kang, Ung Gu

AU - Kim, Yong Sik

AU - Kwon, Taeg Kyu

AU - Han, Mi Young

AU - Kim, Young Ho

AU - Lee, Young Han

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N2 - 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.

AB - 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.

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