Enhancement of fibroblast collagenase-1 (MMP-1) gene expression by tumor promoter okadaic acid is mediated by stress-activated protein kinases Jun N-terminal kinase and p38

Collagenase-1 (matrix metalloproteinase-1, MMP-1) is expressed by several t ypes of cells, including fibroblasts, and apparently plays an important rol e in the remodeling of collagenous extracellular matrix in various physiolo gic and pathologic situations. Here, we have ex amined the molecular mechan isms of the activation of fibroblast MMP-1 gene expression by a naturally o ccurring non-phorbol ester type tumor promoter okadaic acid (OA), a potent inhibitor of serine/threonine protein phosphatase 2A. We show that in fibro blasts OA activates three distinct subgroups of mitogen activated protein k inases (MAPKs): extracellular signal-regulated kinase1,2 (ERK1,2), c-Jun N- terminal-kinase/stress-activated protein kinase (JNK/SAPK) and p38. Activat ion of MMP-1 promoter by OA is entirely blocked by overexpression of dual-s pecificity MAPK phosphatase CL100. In addition, expression of kinase-defici ent forms of ERK1,2, SAP beta, p38, or JNK/SAPK kinase SEK1 strongly inhibi ted OA-elicited activation of MMP-1 promoter. OA-elicited enhancement of MM P-1 mRNA abundance was also strongly prevented by two chemical MAPK inhibit ors: PD 98059, a specific inhibitor of the activation of ERK1,2 kinases MEK 1,2; and SE 203580, a selective inhibitor of p38 activity. Results of this study show that MMP-1 gene expression in fibroblasts is coordinately regula ted by ERK1,2, JNK/SAPK, and p38 MAPKs and suggest an important role for th e stress-activated MAPKs JNK/SAPK and p38 in the activation of MMP-1 gene e xpression. Based on these observations, it is conceivable that specific inh ibition of stress-activated MAPK pathways may serve as a novel therapeutic target for inhibiting degradation of collagenous extracellular matrix.