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Synergistic cooperation between the AP‐1 and LEF‐1 transcription factors in the activation of the matrilysin promoter by the src oncogene: implications in cellular invasion
Author(s) -
Rivat Christine,
Le Floch Nathalie,
Sabbah Michèle,
Teyrol Isabelle,
Redeuilh Gérard,
Bruyneel Erik,
Mareel Marc,
Matrisian Lynn M.,
Crawford Howard C.,
Gespach Christian,
Attoub Samir
Publication year - 2003
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.03-0132fje
Subject(s) - matrilysin , proto oncogene tyrosine protein kinase src , cancer research , oncogene , wnt signaling pathway , transcription factor , biology , chemistry , microbiology and biotechnology , signal transduction , extracellular matrix , gene , cell cycle , biochemistry
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/β‐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 β‐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.