V-SRC ACTIVATION OF THE COLLAGENASE-1 (MATRIX METALLOPROTEINASE-1) PROMOTER THROUGH PEA3 AND STAT - REQUIREMENT OF EXTRACELLULAR SIGNAL-REGULATED KINASES AND INHIBITION BY RETINOIC ACID RECEPTORS

Collagenase-1 (matrix metalloproteinase-1 (MMP-1)) degrades the extrac ellular matrix and enhances the invasive phenotype of tumor cells. v-s rc activated MMP-1 transcription through a series of elements in the p roximal promoter, including the E2BP (nt-172), polyoma virus enhancer A3 (PEA3) (nt-94), activator protein-1 (AP-1) (nt-72), and signal tran sducer and activator of transcription (STAT) (nt-57) consensus sites. Of these sites, PEA3 and STAT contributed specifically to induction by v-src, whereas the remaining elements were also involved in induction by the phorbol ester phorbol myristate acetate (PMA). However, in con trast to MMP-1 induction by PMA, an AP-1 site located at nt-186 did no t contribute to v-src induction. These results suggest divergence of t he tyrosine kinase-and protein kinase C-dependent pathways with respec t to MMP-1 transcription. v-src induced MMP-1 through mitogen-activate d protein kinases, with extracellular signal-regulated kinases playing a larger role than c-jun N-terminal kinase. Retinoic acid, which inhi bits the progression of certain cancers, repressed v-src-induced MMP-1 transcription. Constitutive expression of retinoic acid receptors (RA Rs) alpha or beta, but not gamma, or of retinoid X receptor alpha, rep ressed v-src-induced collagenase-1 transcription. We concluded that on cogenic induction of MMP1 by v-src depends on signaling pathways and c is-acting sequences that are distinct from those involved in phorbol e ster activation. Furthermore, v-src induction of MMP-7 may, by acting in concert with other genes, enhance matrix degradation and tumor prog ression, and retinoic acid and RARs may antagonize this induction in a n RAR type-specific manner. (C) 1998 Wiley-Liss. Inc.