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This Article Full Text Full Text (PDF) All Versions of this Article: 288/1/L190    most recent 00448.2003v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (21) Citing Articles via Google Scholar Google Scholar Articles by Bogatkevich, G. S. Articles by Ludwicka-Bradley, A. Search for Related Content PubMed PubMed Citation Articles by Bogatkevich, G. S. Articles by Ludwicka-Bradley, A.

Distinct PKC isoforms mediate cell survival and DNA synthesis in thrombin-induced myofibroblasts

Division of Rheumatology and Immunology, Departments of ¹Medicine and ³Pathology, Medical University of South Carolina, Charleston, South Carolina; and ²School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania

Submitted 19 December 2003 ; accepted in final form 17 September 2004

Thrombin activates protease-activated receptor (PAR)-1 and induces a myofibroblast phenotype in normal lung fibroblasts that resembles the phenotype of scleroderma lung fibroblasts. We now demonstrate that PAR-1 expression is dramatically increased in lung tissue from scleroderma patients, where it is associated with inflammatory and fibroproliferative foci. We also observe that thrombin induces resistance to apoptosis in normal lung fibroblasts, and this process is regulated by protein kinase C (PKC)- but not by PKC-. Overexpression of a constitutively active (c-a) form of PAR-1 or PKC- significantly inhibits Fas ligand-induced apoptosis in lung fibroblasts, whereas scleroderma lung fibroblasts are resistant to apoptosis de novo. Thrombin translocates p21Cip1/WAF1, a signaling molecule downstream of PKC, from the nucleus to cytoplasm in normal lung fibroblasts mimicking the localization of p21Cip1/WAF1 in scleroderma lung fibroblasts. Overexpression of c-a PKC- or PKC- results in accumulation of p21Cip1/WAF1 in the cytoplasm. Depletion of PKC- or inhibition of mitogen-activated protein kinase (MAPK) blocks thrombin-induced DNA synthesis in lung fibroblasts. Inhibition of PKC by calphostin or PKC-, but not PKC-, by antisense oligonucleotides prevents thrombin-induced MAPK phosphorylation and accumulation of G₁ phase regulatory protein cyclin D1, suggesting that PKC-, MAPK, and cyclin D1 mediate lung fibroblast proliferation. These data demonstrate that two distinct PKC isoforms mediate thrombin-induced resistance to apoptosis and proliferation and suggest that p21Cip1/WAF1 promotes both phenomena.

scleroderma; apoptosis; p21Cip1/WAF1; mitogen-activated protein kinase; cyclin D1; deoxyribonucleic acid; protein kinase C

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