Differential modulation of human fibroblast and keratinocyte growth by the protein kinase C inhibitor GF 109203X.
Protein kinase C (PKC) is known to be involved in cellular proliferation and differentiation. In this work, we have investigated the effects of a novel PKC inhibitor, GF 109203X, on normal human fibroblast and keratinocyte growth. GF 109203X selectively inhibited PKC activity extracted from either fibroblasts (IC50 = 0.01 microM) or keratinocytes (IC50 = 0.4 microM). The inhibitory effects of GF 109203X on total PKC activity and Ca(2+)-independent PKC activity were similar. Nevertheless, in keratinocytes Ca(2+)-independent PKC activity represented 95% of total PKC activity, whereas in fibroblasts it corresponded to only 32% of total PKC activity. GF 109203X also inhibited a cellular function related to PKC activity in living fibroblasts and keratinocytes; it blocked the inhibitory effect of 12-O-tetradecanoylphorbol-13-acetate on 125I-epidermal growth factor binding. GF 109203X inhibited fibroblast growth, in terms of tritiated thymidine incorporation and cell counts, in a dose-dependent manner. We also observed that GF 109203X at 1 microM inhibited serum stimulation of expression of mRNA for c-fos and c-jun, which are usually involved in cellular proliferation. These results suggest that PKC stimulates fibroblast growth. In contrast, GF 109203X stimulated keratinocyte growth. We also observed that GF 109203X inhibited c-fos and c-jun mRNA expression in these cells. In fact, in keratinocytes these proto-oncogenes would be involved in the cellular differentiation process rather than in cellular proliferation. This suggests that the inhibition of PKC favors keratinocyte proliferation probably by inhibiting their differentiation. Thus, using GF 109203X, we show that PKC is involved differently in human fibroblast and keratinocyte growth.
Le Panse
R
R
Unité INSERM 312, Hôpital Henri Mondor, Créteil, France.
Coulomb
B
B
Mitev
V
V
Bouchard
B
B
Lebreton
C
C
Dubertret
L
L
D000293:Adolescent; D000328:Adult; D015152:Blotting, Northern; D047390:Casein Kinase II; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D016762:Genes, fos / Q000235:genetics; D016758:Genes, jun / Q000235:genetics; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000235:genetics; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D008301:Maleimides / Q000494:pharmacology*; D008875:Middle Aged; D011485:Protein Binding / Q000187:drug effects; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D007211:Indoles; D008301:Maleimides; D012333:RNA, Messenger; D004815:Epidermal Growth Factor; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D047390:Casein Kinase II; D017346:Protein Serine-Threonine Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; C070515:bisindolylmaleimide I; D013755:Tetradecanoylphorbol Acetate