Activation of extracellular signal-regulated kinase 1/2 inhibits type I collagen expression by human skin fibroblasts.
Treatment with the lipid second messenger, ceramide, activates extracellular signal-regulated kinase-1/2 (ERK1/2), c-Jun N-terminal kinase, and p38 in human skin fibroblasts and induces their collagenase-1 expression (Reunanen, N., Westermarck, J., Häkkinen, L., Holmström, T. H., Elo, I., Eriksson, J. E., and Kähäri, V.-M. (1998) J. Biol. Chem. 273, 5137-5145). Here we show that C(2)-ceramide inhibits expression of type I and III collagen mRNAs in dermal fibroblasts, suppresses proalpha2(I) collagen promoter activity, and reduces stability of type I collagen mRNAs. The down-regulatory effect of C(2)-ceramide on type I collagen mRNA levels was abrogated by protein kinase C inhibitors H7, staurosporine, and Ro-31-8220 and potently inhibited by a combination of MEK1,2 inhibitor PD98059 and p38 inhibitor SB203580. Activation of ERK1/2 by adenovirus-mediated expression of constitutively active MEK1 resulted in marked down-regulation of type I collagen mRNA levels and production in fibroblasts, whereas activation of p38 by constitutively active MAPK kinase-3b and MAPK kinase-6b slightly up-regulated type I collagen expression. These results identify the ERK1/2 signaling cascade as a potent negative regulatory pathway with respect to type I collagen expression in fibroblasts, suggesting that it mediates inhibition of collagen production in response to mitogenic stimulation and transformation.
Reunanen
N
N
Turku Centre for Biotechnology, University of Turku, Finland.
Foschi
M
M
Han
J
J
Kahari
V M
VM
D016475:3T3 Cells; D000818:Animals; D002478:Cells, Cultured; D003094:Collagen / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012867:Skin / Q000166:cytology / Q000378:metabolism*
D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D003094:Collagen; D011493:Protein Kinase C; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases