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Expression of collagenase-3 (MMP-13) and collagenase-1 (MMP-1) by transformed keratinocytes is dependent on the activity of p38 mitogen-activated protein kinase.
J Cell Sci 2000; 113 Pt 2:227-35JC

Abstract

Collagenase-3 (MMP-13) is a human matrix metalloproteinase specifically expressed by transformed squamous epithelial cells, i.e. squamous cell carcinoma (SCC) cells in culture and in vivo. Here, we have elucidated the signaling pathways regulating MMP-13 expression in transformed human epidermal keratinocytes, i.e. ras-transformed HaCaT cell line A-5 and cutaneous SCC cell line (UT-SCC-7). Treatment with tumor necrosis factor-(alpha) (TNF-(alpha) resulted in activation of extracellular signal-regulated kinase (ERK)1,2, Jun N-terminal kinase and p38 mitogen-activated protein kinase (MAPK) in both cell lines. In addition, transforming growth factor-(beta) (TGF-(beta) activated p38 MAPK in both cell lines, and ERK2 in A-5 cells. Selective inhibition of p38 activity with SB 203580 abolished the enhancement of MMP-13, as well as collagenase-1 (MMP-1) and 92-kDa gelatinase (MMP-9) expression by TNF-(alpha) and TGF-(beta). Blocking the ERK1, 2 pathway by PD 98059 had no effect on the induction of MMP-13 expression by TNF-(alpha) or TGF-(beta), but potently suppressed MMP-1 and MMP-9 production. Inhibition of p38 activity by SB 203580 also suppressed collagenolytic activity produced by both cell lines and inhibited invasion of TNF-(alpha) or TGF-(beta) stimulated A-5 cells through type I collagen and reconstituted basement membrane (Matrigel). These results show that activation of p38 MAPK pathway plays a crucial role in the invasive phenotype of transformed squamous epithelial cells, suggesting p38 MAPK as a target to specifically inhibit their invasion.

Authors+Show Affiliations

MediCity Research Laboratory and Department of Medical Biochemistry, University of Turku, FIN-20520 Turku, Finland.No affiliation info availableNo 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

10633074

Citation

Johansson, N, et al. "Expression of Collagenase-3 (MMP-13) and Collagenase-1 (MMP-1) By Transformed Keratinocytes Is Dependent On the Activity of P38 Mitogen-activated Protein Kinase." Journal of Cell Science, vol. 113 Pt 2, 2000, pp. 227-35.
Johansson N, Ala-aho R, Uitto V, et al. Expression of collagenase-3 (MMP-13) and collagenase-1 (MMP-1) by transformed keratinocytes is dependent on the activity of p38 mitogen-activated protein kinase. J Cell Sci. 2000;113 Pt 2:227-35.
Johansson, N., Ala-aho, R., Uitto, V., Grénman, R., Fusenig, N. E., López-Otín, C., & Kähäri, V. M. (2000). Expression of collagenase-3 (MMP-13) and collagenase-1 (MMP-1) by transformed keratinocytes is dependent on the activity of p38 mitogen-activated protein kinase. Journal of Cell Science, 113 Pt 2, pp. 227-35.
Johansson N, et al. Expression of Collagenase-3 (MMP-13) and Collagenase-1 (MMP-1) By Transformed Keratinocytes Is Dependent On the Activity of P38 Mitogen-activated Protein Kinase. J Cell Sci. 2000;113 Pt 2:227-35. PubMed PMID: 10633074.
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TY - JOUR T1 - Expression of collagenase-3 (MMP-13) and collagenase-1 (MMP-1) by transformed keratinocytes is dependent on the activity of p38 mitogen-activated protein kinase. AU - Johansson,N, AU - Ala-aho,R, AU - Uitto,V, AU - Grénman,R, AU - Fusenig,N E, AU - López-Otín,C, AU - Kähäri,V M, PY - 2000/1/14/pubmed PY - 2000/3/25/medline PY - 2000/1/14/entrez SP - 227 EP - 35 JF - Journal of cell science JO - J. Cell. Sci. VL - 113 Pt 2 N2 - Collagenase-3 (MMP-13) is a human matrix metalloproteinase specifically expressed by transformed squamous epithelial cells, i.e. squamous cell carcinoma (SCC) cells in culture and in vivo. Here, we have elucidated the signaling pathways regulating MMP-13 expression in transformed human epidermal keratinocytes, i.e. ras-transformed HaCaT cell line A-5 and cutaneous SCC cell line (UT-SCC-7). Treatment with tumor necrosis factor-(alpha) (TNF-(alpha) resulted in activation of extracellular signal-regulated kinase (ERK)1,2, Jun N-terminal kinase and p38 mitogen-activated protein kinase (MAPK) in both cell lines. In addition, transforming growth factor-(beta) (TGF-(beta) activated p38 MAPK in both cell lines, and ERK2 in A-5 cells. Selective inhibition of p38 activity with SB 203580 abolished the enhancement of MMP-13, as well as collagenase-1 (MMP-1) and 92-kDa gelatinase (MMP-9) expression by TNF-(alpha) and TGF-(beta). Blocking the ERK1, 2 pathway by PD 98059 had no effect on the induction of MMP-13 expression by TNF-(alpha) or TGF-(beta), but potently suppressed MMP-1 and MMP-9 production. Inhibition of p38 activity by SB 203580 also suppressed collagenolytic activity produced by both cell lines and inhibited invasion of TNF-(alpha) or TGF-(beta) stimulated A-5 cells through type I collagen and reconstituted basement membrane (Matrigel). These results show that activation of p38 MAPK pathway plays a crucial role in the invasive phenotype of transformed squamous epithelial cells, suggesting p38 MAPK as a target to specifically inhibit their invasion. SN - 0021-9533 UR - https://www.unboundmedicine.com/medline/citation/10633074/Expression_of_collagenase_3__MMP_13__and_collagenase_1__MMP_1__by_transformed_keratinocytes_is_dependent_on_the_activity_of_p38_mitogen_activated_protein_kinase_ L2 - http://jcs.biologists.org/cgi/pmidlookup?view=long&pmid=10633074 DB - PRIME DP - Unbound Medicine ER -