Parathyroid hormone co-stimulation of hepatocyte proliferation is sensitive to protein kinase A and calcium channel inhibitors.
Parathyroid hormone (PTH) mobilises calcium in the hepatocyte, an effect which is abolished by verapamil and staurosporine. In our study parathyroid hormone was shown to act additively to dHGF in inducing hepatocyte DNA synthesis. It is also shown that PTH induced the production of inositol 1,4,5 trisphosphate (IP3) and c-fos expression at early times in culture. Co-incubation of PTH and dHGF with a c-fos antisense oligodeoxynucleotide inhibited hepatocyte DNA synthesis, indicating that the additive effect of PTH is correlated with the induction of c-fos. H-89, a PKA specific inhibitor, inhibited the PTH effect on IP3 production as well as the PTH effect on hepatocyte DNA synthesis. Verapamil and staurosporine also inhibited the PTH effect in dHGF-induced DNA synthesis. Therefore it is suggested that PKA mediated at a great extent the co-stimulatory effects of PTH on hepatocyte proliferation via IP3 production.
Deutsches Krebsforschungszentrum, Department of Applied Tumour Virology, Heidelberg, Germany.
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D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors*; D004247:DNA / Q000096:biosynthesis; D017228:Hepatocyte Growth Factor / Q000494:pharmacology; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000096:biosynthesis; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010281:Parathyroid Hormone / Q000494:pharmacology*; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D051381:Rats
D002121:Calcium Channel Blockers; D016376:Oligonucleotides, Antisense; D010281:Parathyroid Hormone; D016760:Proto-Oncogene Proteins c-fos; D017228:Hepatocyte Growth Factor; D015544:Inositol 1,4,5-Trisphosphate; D004247:DNA; D017868:Cyclic AMP-Dependent Protein Kinases