Heparin down-regulates the phorbol ester-induced protein kinase C gene expression in human endothelial cells: enzyme-mediated autoregulation of protein kinase C-alpha and -delta genes.
Overexpression of protein kinase C-alpha and protein kinase C-delta has been shown to modulate a number of biological effects, including the cell growth and differentiation. We hypothesized that heparin, a potent antimitogenic drug, could affect the cell proliferation by inhibiting the expression of specific protein kinase C genes. Heparin, markedly but not completely, inhibited the serum-stimulated protein kinase C-alpha and -delta mRNA expression. Protein kinase C inhibition or down-regulation significantly decreased the serum-induced protein kinase C isoenzyme gene expression. Heparin failed to inhibit the residual effect of serum that was resistant to the above-mentioned treatments. Phorbol 12-myristate 13-acetate elicited an increase of protein kinase C isoenzyme gene expression that was completely prevented by protein kinase C inhibition or down-regulation. Heparin dose-dependently counteracted and ultimately abolished the increase in the protein kinase C isoenzyme gene expression elicited by phorbol 12-myristate 13-acetate. These results suggest that the inhibition of an autoregulatory role wielded by protein kinase C on the protein kinase C-alpha and -delta gene expression might represent a possible mechanism by which glycosaminoglycans modulate the cell growth.
Pintus
G
G
National Laboratory of the National Institute of Biostructures and Biosystems, Osilo, Italy. gpintus@ssmain.uniss.it
Tadolini
B
B
Maioli
M
M
Posadino
A M
AM
Gaspa
L
L
Ventura
C
C
D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects; D004730:Endothelium, Vascular / Q000166:cytology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006493:Heparin / Q000378:metabolism* / Q000494:pharmacology; D006706:Homeostasis; D006801:Humans; D007527:Isoenzymes / Q000235:genetics*; D011493:Protein Kinase C / Q000235:genetics*; D051571:Protein Kinase C-alpha; D051745:Protein Kinase C-delta; D013755:Tetradecanoylphorbol Acetate / Q000378:metabolism* / Q000494:pharmacology
D007527:Isoenzymes; D006493:Heparin; C496628:PRKCA protein, human; C497258:PRKCD protein, human; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha; D051745:Protein Kinase C-delta; D013755:Tetradecanoylphorbol Acetate