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

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.

Physical and functional cooperation between AP-1 and β-catenin for the regulation of TCF-dependent genes

“…This mechanism involved TCF4 interaction with phospho-c-Jun on the proximal AP-1 element of the promoter, required the presence of both the TCF and the AP-1 sites, and was not inhibited by TCF4DN as in our present study (Nateri et al, 2005). The interaction of c-Jun with LEF-1, another protein of the TCF family, has also been described on the AP-1 site of the matrilysin promoter (Rivat et al, 2003). Whether the molecular mechanisms underlying the AP-1 functional cooperation vary between the cyclin D1 and the c-myc promoter, as suggested by the stronger stimulating effect of AP-1 on the latter, are not clear.…”

“…Specifically, c-Jun has been shown to physically interact with LEF-1, leading to a synergistic transactivation of the matrilysin promoter (Rivat et al, 2003). Interaction of phosphorylated c-Jun with TCF4 on AP-1-binding sites was reported to be involved in the proliferation of colonic carcinoma cells (Nateri et al, 2005).…”

Opposing roles of netrin-1 and the dependence receptor DCC in cancer cell invasion, tumor growth and metastasis

“…We confirmed the invasion suppressive functions of DCC in metastatic MDCKts.src-ggl.wt-DCC cells showing that DCC remarkably exerts dominant functions over the src oncogene. The src tyrosine kinase is activated at early stages during colon cancer progression and plays major roles in cancer cell survival and invasion (Rivat et al, 2003). We found that wt-DCC significantly reduced the number of luciferasepositive MDCKts.src-ggl cancer cells in primary tumors, suggesting that DCC expression alters their viability and survival in the tumor microenvironment.…”

Commutators of PAR-1 signaling in cancer cell invasion reveal an essential role of the Rho–Rho kinase axis and tumor microenvironment

“…Moreover, MMP-1 is a new breast cancer predictive marker to identify patients with lesions that may develop into cancer (Poola et al, 2005). There are some early clues suggesting that the RhoA-ROK axis is also connected with JNK-and c-Jun/AP-1-dependent transcription (Marinissen et al, 2004) involved in several proinvasive pathways, including src and Wnt (Rivat et al, 2003;Le Floch et al, 2005). In the present study, we have clearly shown that several PAR-1 commutators are acting as invasion promoters through the cGMP/PKG cascade and inhibition of the RhoA/ ROK axis.…”