Essential role of mitogen-activated protein kinase pathway and c-Jun induction in epidermal growth factor-induced gene expression of human 12- lipoxygenase

Ben Kuen Chen, Hui Chung Kung, Tein Yi Tsai, Wen Chang Chang

Research output: Contribution to journalArticlepeer-review

29 Citations (Scopus)

Abstract

The role of mitogen-activated protein kinase signaling and the transcription factor c-Jun in epidermal growth factor (EGF)-induced expression of 12-lipoxygenase in human epidermoid carcinoma A431 cells was studied. EGF increased the activation of extracellular signal-regulated kinase (ERK) and c-Jun amino terminal kinase (JNK) in a time-dependent manner. Treatment of the cells with an mitogen-activated protein kinase kinase inhibitor, PD098059 (30 μM), inhibited the EGF- and pSV2ras-induced expression of 12-lipoxygenase mRNA. Transfection of the cells with Ras, ERK2, Rac, JNK dominant negative mutants pMMrasDN, K52R ERK2, RacN17, and mJNK all inhibited the EGF-induced promoter activation of the 12-lipoxygenase gene. EGF induced the expression of c-Jun and the activity of transcription factor activator protein 1 in cells, and these effects were blocked by the treatment with K52R ERK2 and mJNK. Overexpression of c-Jun increased the expression of 12-lipoxygenase mRNA and enzyme activity. Furthermore, the Sp1-binding sites in the promoter region of the 12-lipoxygenase gene were requisite for c-Jun response, which was similar to that previously observed in EGF response. The results indicate that the EGF-induced expression of 12-lipoxygenase in A431 cells was mediated through the Ras-ERK and Ras-Rac-JNK signal pathways. Subsequent induction of c-Jun led by ERK and JNK activation was essential for this EGF response.

Original languageEnglish
Pages (from-to)153-161
Number of pages9
JournalMolecular Pharmacology
Volume57
Issue number1
Publication statusPublished - 2000
Externally publishedYes

ASJC Scopus subject areas

  • Pharmacology

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