Synergistic cooperation between the AP-1 and LEF-1 transcription factors in activation of the matrilysin promoter by the src oncogene: implications in cellular invasion.

Christine Rivat, Nathalie Le Floch, Michèle Sabbah, Isabelle Teyrol, Gérard Redeuilh, Erik Bruyneel, Marc Mareel, Lynn M. Matrisian, Howard C. Crawford, Christian Gespach, Samir Attoub

Research output: Contribution to journalArticle

65 Scopus citations

Abstract

The matrix metalloprotease matrilysin is expressed in premalignant polyps and plays a key role in local invasion during the progression of digestive tumors. In the present work, we investigated the possible relationships between the activity of the mouse and human matrilysin promoters (Mp), endogenous matrilysin protein expression, and two early oncogenetic defects frequently observed in human colonic cancers, namely activation of the src oncogene and impairment of the Wnt/APC/beta-catenin pathway. Using transient transfection assays, we report here that src signaling and the HMG-box transcription factor LEF-1 act synergistically with the proximal (-61 to -67) AP-1 binding site to transactivate the Mp in premalignant and tumorigenic kidney and colonic epithelial cells, through beta-catenin- and axin-independent signaling pathways. This synergism involves the -109 and -194 Tcf/LEF-1 binding sites in the Mp and a physical interaction between LEF-1 and c-Jun. Furthermore, src coordinates accumulation of the c-Jun factor and matrilysin transcripts. Conversely, the c-Jun dominant negative mutant TAM67 and the src tyrosine kinase inhibitor M475271 impaired src-induced Mp activation, matrilysin protein accumulation, and invasion of type I collagen gels. This mechanism may thereby contribute to cellular invasion during the early-stage adenoma/adenocarcinoma conversion and the metastatic process of digestive tumors.

Original languageEnglish (US)
Pages (from-to)1721-1723
Number of pages3
JournalThe FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume17
Issue number12
DOIs
StatePublished - Sep 2003

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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