Collagenase-1 (matrix metalloproteinase-1 (MMP-1)) degrades the extracellular matrix and enhances the invasive phenotype of
tumor cells. v-src activated MMP-1 transcription through a series of elements in the proximal promoter, including the E2BP (nt -172), polyoma virus enhancer A3 (PEA3) (nt -94),
activator protein-1 (AP-1) (nt -72), and signal transducer 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 contrast to MMP-1 induction by PMA, an
AP-1 site located at nt -186 did not contribute to v-src induction. These results suggest divergence of the
tyrosine kinase- and
protein kinase C-dependent pathways with respect to MMP-1 transcription. v-src induced MMP-1 through
mitogen-activated protein kinases, with
extracellular signal-regulated kinases playing a larger role than
c-jun N-terminal kinase.
Retinoic acid, which inhibits the progression of certain
cancers, repressed v-src-induced MMP-1 transcription. Constitutive expression of
retinoic acid receptors (RARs) alpha or beta, but not gamma, or of
retinoid X receptor alpha, repressed v-src-induced
collagenase-1 transcription. We concluded that oncogenic induction of MMP-1 by v-src depends on signaling pathways and cis-acting sequences that are distinct from those involved in
phorbol ester activation. Furthermore, v-src induction of MMP-1 may, by acting in concert with other genes, enhance matrix degradation and
tumor progression, and
retinoic acid and RARs may antagonize this induction in an RAR type-specific manner.