CROSS-TALK BETWEEN DIFFERENT ENHANCER ELEMENTS DURING MITOGENIC INDUCTION OF THE HUMAN STROMELYSIN-1 GENE

Platelet-derived growth factor (PDGF) induces the expression of human stromelysin-1, a matrix metalloproteinase involved in tumor invasion a nd metastasis. Here it is shown that stromelysin-1 gene induction by P DGF depends on Ras and involves three previously identified promoter e lements (the stromelysin-1 PDGF-responsive element (SPRE) site, the tw o head to-head polyomavirus enhancer A-binding protein 3 (PEA3) sites, and the activator protein-1 (AP-1) binding site). During mitogenic in duction, these responsive elements appear to be organized in two indep endent transcriptional units, SPRE-AP-1 and PEA3-AP-1, which result fr om specific element cross talking. Interestingly, expression of a domi nant negative mutant of Raf-1 significantly interfered with the induct ion through PEA3-AP-1 but not with that operating through SPRE-AP-1. C onversely, only the induction operating through SPRE-AP-1 was affected significantly by the expression of a dominant negative mutant of the atypical lambda/iota protein kinase C (lambda/iota PKC). These data st rongly suggest that the signal triggered by PDGF flows through Ras and bifurcates toward two distinct pathways, one operating through Raf an d involving PEA3-AP-1 and the other one Raf-independent, operating thr ough lambda/iota PKC and SPRE-AP-1. Furthermore, we present evidence s uggesting that the novel SPRE-binding transcription factor SPBP cross- couples with c-Jun to transactivate the SPRE site.