title: 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.
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.
authors.affiliation: INSERM U 482, Hôpital Saint-Antoine, 75571, Paris Cedex 12, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Rivat
authors.forename: Nathalie
authors.initials: N
authors.lastname: Le Floch
authors.forename: Michèle
authors.initials: M
authors.lastname: Sabbah
authors.forename: Isabelle
authors.initials: I
authors.lastname: Teyrol
authors.forename: Gérard
authors.initials: G
authors.lastname: Redeuilh
authors.forename: Erik
authors.initials: E
authors.lastname: Bruyneel
authors.forename: Marc
authors.initials: M
authors.lastname: Mareel
authors.forename: Lynn M
authors.initials: LM
authors.lastname: Matrisian
authors.forename: Howard C
authors.initials: HC
authors.lastname: Crawford
authors.forename: Christian
authors.initials: C
authors.lastname: Gespach
authors.forename: Samir
authors.initials: S
authors.lastname: Attoub
mesh_terms: D003110:Colonic Neoplasms / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004790:Enzyme Induction; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051821:Lymphoid Enhancer-Binding Factor 1; D020783:Matrix Metalloproteinase 7 / Q000235:genetics*; D008954:Models, Biological; D009361:Neoplasm Invasiveness; D015688:Oncogene Protein pp60(v-src) / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D020218:Response Elements; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured
chemical_list: D004268:DNA-Binding Proteins; C497573:LEF1 protein, human; D051821:Lymphoid Enhancer-Binding Factor 1; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D015688:Oncogene Protein pp60(v-src); D020783:Matrix Metalloproteinase 7