Activation of p38α MAPK Enhances Collagenase-1 (Matrix Metalloproteinase (MMP)-1) and Stromelysin-1 (MMP-3) Expression by mRNA Stabilization

Niina Reunanen,Song-Ping Li,Matti Ahonen,Marco Foschi,Jiahuai Han,Veli-Matti Kähäri

doi:10.1074/jbc.m204296200

Niina Reunanen, Song-Ping Li + Show 4 more

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https://doi.org/10.1074/jbc.m204296200

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Abstract

Here, we have examined the role of distinct MAPK pathways in the regulation of collagenase-1 (matrix metalloproteinase (MMP)-1) and stromelysin-1 (MMP-3) expression by human skin fibroblasts. Tumor necrosis factor-alpha rapidly and transiently activated ERK1/2 and JNK in fibroblasts, whereas the activation of p38 MAPK was more persistent. Inhibition of p38 activity by SB203580 markedly (by 80-90%) inhibited induction of MMP-1 and MMP-3 expression by tumor necrosis factor-alpha, whereas blocking the activation of ERK1/2 by PD98059 had no effect. Activation of endogenous ERK1/2 by adenovirus-mediated transfer of constitutively active MEK1 resulted in potent induction of MMP-1 and MMP-3 expression. Activation of endogenous or adenovirally expressed p38 alpha by adenovirally delivered constitutively active MKK3b and MKK6b also enhanced MMP-1 and MMP-3 expression and augmented the up-regulatory effect of ERK1/2 activation on the expression of these MMPs. Activation of ERK1/2 resulted in induction of c-jun, junB, and c-fos expression, whereas activation of p38 alone had no effect. In contrast, activation of p38 alpha resulted in marked stabilization of MMP-1 and MMP-3 mRNAs. These results identify two distinct and complementary signaling mechanisms mediating induction of MMP-1 and MMP-3 expression in dermal fibroblasts: AP-1-dependent transcriptional activation via the ERK1/2 pathway and AP-1-independent enhancement via p38 alpha MAPK by mRNA stabilization. It is conceivable that both modes of action play an important role in controlling the proteolytic phenotype of fibroblasts, e.g. in wound repair and tumor invasion.

Highlights

We have examined the role of distinct mitogen-activated protein kinases (MAPKs) pathways in the regulation of collagenase-1 (matrix metalloproteinase (MMP)-1) and stromelysin-1 (MMP-3) expression by human skin fibroblasts
Our recent results show that the activation of ERK1/2 alone potently enhances Matrix metalloproteinases (MMPs)-1 promoter activity, whereas activation of p38 extracellular matrix; MAPK, mitogen-activated protein kinase; ERK, extracellular signal-regulated kinase; JNK, c-Jun N-terminal kinase; MKK, MAPK kinase; MEK, MAPK/ERK kinase; TNF-␣, tumor necrosis factor-␣; DRB, 5,6-dichloro-1-b(␤)-D-ribofuranosylbenzimidazole; DMEM, Dulbecco’s modified Eagle’s medium; FCS, fetal calf serum; TIMP, tissue inhibitor of metalloproteinase; glyceraldehyde-3phosphate dehydrogenase (GAPDH), glyceraldehyde3-phosphate dehydrogenase; MOPS, 4-morpholinepropanesulfonic acid; CREB, cAMP response element-binding protein; ATF, activating transcription factor; NF-␬B, nuclear factor-␬B; m.o.i., multiplicity of infection
These results provide evidence for two distinct and complementary mechanisms mediating induction of the collagenolytic capacity of dermal fibroblasts: AP-1-dependent transcriptional activation of MMP-1 gene expression via the ERK1/2 pathway and AP-1independent enhancement via p38 MAPK by mRNA stabilization, suggesting that both play an important role in controlling the proteolytic phenotype of fibroblasts, e.g. in wound repair and tumor invasion

Summary

Introduction

We have examined the role of distinct MAPK pathways in the regulation of collagenase-1 (matrix metalloproteinase (MMP)-1) and stromelysin-1 (MMP-3) expression by human skin fibroblasts. These results provide evidence for two distinct and complementary mechanisms mediating induction of the collagenolytic capacity of dermal fibroblasts: AP-1-dependent transcriptional activation of MMP-1 gene expression via the ERK1/2 pathway and AP-1independent enhancement via p38 MAPK by mRNA stabilization, suggesting that both play an important role in controlling the proteolytic phenotype of fibroblasts, e.g. in wound repair and tumor invasion.

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Conclusion