Role of protein kinase C-delta in the regulation of collagen gene expression in scleroderma fibroblasts

Citation
Sa. Jimenez et al., Role of protein kinase C-delta in the regulation of collagen gene expression in scleroderma fibroblasts, J CLIN INV, 108(9), 2001, pp. 1395-1403
Citations number
47
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Medical Research General Topics
Journal title
JOURNAL OF CLINICAL INVESTIGATION
ISSN journal
0021-9738 → ACNP
Volume
108
Issue
9
Year of publication
2001
Pages
1395 - 1403
Database
ISI
SICI code
0021-9738(200111)108:9<1395:ROPKCI>2.0.ZU;2-O
Abstract
Working with cultured dermal fibroblasts derived from control individuals a nd patients with systemic sclerosis (SSc), we have examined the effects of protein kinase C-delta (PKC-delta) on type I collagen biosynthesis and stea dy-state levels of COL1A1 and COL3A1 mRNAs. Rottlerin, a specific inhibitor of PKC-delta, exerted a powerful, dose-dependent inhibition of type I and type III collagen gene expression in normal and SSc cells. Optimal rottleri n concentrations caused a 70-90% inhibition of type I collagen production, a >80% reduction in COL1A1 mRNA, and a >70% reduction in COL3A1 mRNA in bot h cell types. In vitro nuclear transcription assays and transient transfect ions with COL1A1 promoter deletion constructs demonstrated that rottlerin p rofoundly reduced COL1A1 transcription and that this effect required a 129- bp promoter region encompassing nucleotides -804 to -675. This COL1A1 segme nt imparted rottlerin sensitivity to a heterologous promoter. Cotransfectio ns of COL1A1 promoter constructs with a dominant-negative PKC-delta express ion plasmid showed that suppression of this kinase silenced COL1A1 promoter activity. The results indicate that PKC-delta participates in the upregula tion of collagen gene transcription in SSc and suggest that treatment with PKC-delta inhibitors could suppress fibrosis in this disease.