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Activation of p38 alpha MAPK enhances collagenase-1 (matrix metalloproteinase (MMP)-1) and stromelysin-1 (MMP-3) expression by mRNA stabilization.
J Biol Chem. 2002 Aug 30; 277(35):32360-8.JB

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.

Authors+Show Affiliations

Centre for Biotechnology and Department of Medicinal Biochemistry, University of Turku, FIN-20520 Turku, Finland.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

12060661

Citation

Reunanen, Niina, et al. "Activation of P38 Alpha MAPK Enhances Collagenase-1 (matrix Metalloproteinase (MMP)-1) and Stromelysin-1 (MMP-3) Expression By mRNA Stabilization." The Journal of Biological Chemistry, vol. 277, no. 35, 2002, pp. 32360-8.
Reunanen N, Li SP, Ahonen M, et al. Activation of p38 alpha MAPK enhances collagenase-1 (matrix metalloproteinase (MMP)-1) and stromelysin-1 (MMP-3) expression by mRNA stabilization. J Biol Chem. 2002;277(35):32360-8.
Reunanen, N., Li, S. P., Ahonen, M., Foschi, M., Han, J., & Kähäri, V. M. (2002). Activation of p38 alpha MAPK enhances collagenase-1 (matrix metalloproteinase (MMP)-1) and stromelysin-1 (MMP-3) expression by mRNA stabilization. The Journal of Biological Chemistry, 277(35), 32360-8.
Reunanen N, et al. Activation of P38 Alpha MAPK Enhances Collagenase-1 (matrix Metalloproteinase (MMP)-1) and Stromelysin-1 (MMP-3) Expression By mRNA Stabilization. J Biol Chem. 2002 Aug 30;277(35):32360-8. PubMed PMID: 12060661.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Activation of p38 alpha MAPK enhances collagenase-1 (matrix metalloproteinase (MMP)-1) and stromelysin-1 (MMP-3) expression by mRNA stabilization. AU - Reunanen,Niina, AU - Li,Song-Ping, AU - Ahonen,Matti, AU - Foschi,Marco, AU - Han,Jiahuai, AU - Kähäri,Veli-Matti, Y1 - 2002/06/11/ PY - 2002/6/13/pubmed PY - 2002/10/18/medline PY - 2002/6/13/entrez SP - 32360 EP - 8 JF - The Journal of biological chemistry JO - J. Biol. Chem. VL - 277 IS - 35 N2 - 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. SN - 0021-9258 UR - https://www.unboundmedicine.com/medline/citation/12060661/Activation_of_p38_alpha_MAPK_enhances_collagenase_1__matrix_metalloproteinase__MMP__1__and_stromelysin_1__MMP_3__expression_by_mRNA_stabilization_ L2 - http://www.jbc.org/cgi/pmidlookup?view=long&pmid=12060661 DB - PRIME DP - Unbound Medicine ER -