Src oncogene activates MMP-2 expression via the ERK/Sp1 pathway

Lunyu Kuo, Hui Chiu Chang, Tzeng Horng Leu, Ming Chie Maa, Wen Chun Hung

Research output: Contribution to journalArticle

62 Citations (Scopus)

Abstract

Previous studies demonstrated that activation of Src oncogene increased matrix metalloproteinase-2 (MMP-2) expression in various types of cells. In this study, we elucidated the underlying mechanism of Src-induced MMP-2. We first used murine fibroblast cell line C3H10T1/2 and its v-Src transfectant IV5 to address this issue. RT-PCR and promoter activity assay indicated that Src stimulated MMP-2 via transcriptional activation. Transfection of constitutively active Src into C3H10T1/2 cells also stimulated MMP-2 mRNA expression. Deletion and mutation analysis indicated that the Sp1 site located within the -91/-84 region of human MMP-2 promoter is the major responsive element for Src. Electrophoresis mobility shift assays showed that Src enhanced the binding of Sp1 to this consensus site to stimulate MMP-2 gene expression. We next investigated the signaling pathway that mediated the effect of Src on MMP-2. Our data showed that extracellular signal-regulated kinase (ERK) pathway inhibitor PD98059, but not the c-Jun N-terminal kinase (JNK) inhibitor SP600125, p38 kinase inhibitor SB203580, and PI3K inhibitor wortmannin, attenuated Src-induced MMP-2 promoter activity. These inhibitors did not show significant effect on basal MMP-2 promoter activity in C3H10T1/2 cells. In addition, the dominant negative mutant of ERK-2 suppressed the activation of MMP-2 by Src. Treatment of PD98059 or an Src specific inhibitor PP1 reduced Sp1 DNA binding activity in IV5 cells. Taken together, our results strongly suggest that Src induces MMP-2 expression via transcription activation and the ERK/Sp1 signaling pathway is involved in this process.

Original languageEnglish
Pages (from-to)729-734
Number of pages6
JournalJournal of Cellular Physiology
Volume207
Issue number3
DOIs
Publication statusPublished - 2006 Jun 1

All Science Journal Classification (ASJC) codes

  • Physiology
  • Clinical Biochemistry
  • Cell Biology

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