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The p38 SAPK Pathway Regulates the Expression of the MMP-9 Collagenase via AP-1-Dependent Promoter Activation

2001; Elsevier BV; Volume: 271; Issue: 2 Linguagem: Inglês

10.1006/excr.2001.5374

1090-2422

Christian Simon, Matthias Simon, Goran Vucelic, John Hicks, Peter K. Plinkert, Assen Koitschev, H. P. Zenner,

NF-κB Signaling Pathways

The invasive phenotype of cancers critically depends on the expression of proteases such as the MR 92,000 type IV collagenase (MMP-9). Several growth factors and oncogenes were found to increase promoter activity and as a consequence protease expression. This frequently requires the activation of the transcription factor AP-1 by signal transduction cascades such as the ERK and JNK pathways. We have previously demonstrated that the tumor promoter TPA can induce MMP-9 expression via a third signaling cascade, the p38 pathway. Considering that TPA is a potent activator of AP-1, we hypothesized that this transcription factor might also be required for p38 pathway-dependent MMP-9 regulation. While dominant negative p38 and MKK-6 mutants reduced MMP-9 promoter activity in CAT assays, a construct encoding an activating mutation in the MKK-6 protein potently stimulated it. This was mediated via 144 bp of the 5′flanking region of the wild-type promoter, which contains an AP-1 site at −79. Both point mutations in this motif and the expression of a c-jun protein lacking its transactivation domain and therefore acting as a dominant negative AP-1 mutant abrogated MKK-6-dependent promoter stimulation. Finally SB 203580, a specific p38 pathway inhibitor, reduced MMP-9 expression/secretion and in vitro invasion of cancer cells. Thus, our results provide evidence that also the third SAPK/MAPK signaling cascade, the p38 signal transduction pathway, stimulates MMP-9 expression in an AP-1-dependent fashion.