Induction of cyclic AMP synthesis by forskolin is followed by a reduction in the expression of c-myc messenger RNA and inhibition of 3H-thymidine incorporation in human fibroblasts.
We have studied the effect of increased intracellular levels of cyclic AMP on the growth response to platelet-derived growth factor (PDGF) of human foreskin fibroblasts in culture. It was found that forskolin, a potent stimulator of adenylate cyclase activity, inhibits the stimulatory effect of PDGF on 3H-thymidine incorporation with a dose dependence similar to that observed with regard to cyclic AMP formation. A time-course study indicated that forskolin has no effect on ongoing DNA synthesis but affects events in the prereplicative phase. The cell-cycle block induced by forskolin was found to be reversible; after removal of the drug, DNA synthesis was initiated after a lag period, similar to that of the prereplicative phase of control cells. Forskolin had no effect on PDGF binding, receptor autophosphorylation, or c-fos mRNA expression. However, a reduction in PDGF-induced c-myc mRNA expression was observed in cultures given forskolin. Forskolin was also found to have a marked stimulatory effect on the expression of interferon-beta 2 mRNA expression. However, we were unable to demonstrate that the growth-inhibitory effect of forskolin is mediated by interferon-beta. In conclusion, an increase in cAMP levels leads to a reversible inhibition of PDGF-induced DNA synthesis in human fibroblasts, which may be related to an inhibition of c-myc mRNA expression.
Heldin
N E
NE
Department of Pathology, University Hospital, Uppsala, Sweden.
Paulsson
Y
Y
Forsberg
K
K
Heldin
C H
CH
Westermark
B
B
D002460:Cell Line; D005576:Colforsin / Q000494:pharmacology*; D000242:Cyclic AMP / Q000096:biosynthesis*; D005347:Fibroblasts / Q000378:metabolism*; D006801:Humans; D007370:Interferon Type I / Q000235:genetics; D009857:Oncogenes; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism*; D013936:Thymidine / Q000493:pharmacokinetics*
D007370:Interferon Type I; D010982:Platelet-Derived Growth Factor; D012333:RNA, Messenger; D005576:Colforsin; D000242:Cyclic AMP; D013936:Thymidine