Modulation of growth-related gene expression and growth inhibition by cyclic adenosine 3',5'-monophosphate-elevating agents in the insulin-producing cell line beta TC1.
We studied the involvement of the cAMP pathway in the regulation of beta TC1 cell growth with the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX) and the activator of adenylate cyclase forskolin. We examined the effect of the increase in cAMP content on the serum-induced resumption of the cell cycle of quiescent cells. IBMX and forskolin both inhibited the mitogenic effect of serum in a concentration-dependent manner. Intracellular cAMP levels were, respectively, enhanced 3.0- and 8.6-fold by IBMX (0.5 mM) and forskolin (20 microM) within 1 h. IBMX and forskolin were also inducers of insulin release, indicating that the growth-arrested beta TC1 cells have retained the essential characteristics of the normal differentiated beta-cells. The effects of IBMX and forskolin were correlated with a modulation of cell cycle-related gene expression. IBMX induced expression of the c-fos gene, which was further enhanced by the simultaneous addition of serum, whereas forskolin alone elicited maximal induction of this gene. Interestingly, c-jun expression was only enhanced with forskolin. We also studied the effects of IBMX and forskolin on the expression of the simian virus-40 T-antigen controlled by the rat insulin II promoter in beta TC1 cells. IBMX and forskolin inhibited the serum-induced accumulation of simian virus-40 T-antigen mRNA in quiescent as well as exponentially growing beta TC1 cells.
Lavergne
C
C
Unité INSERM 55, Hôpital Saint-Antoine, Paris, France.
Breant
B
B
Rosselin
G
G
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology*; D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000235:genetics; D002453:Cell Cycle; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D005576:Colforsin / Q000494:pharmacology*; D000242:Cyclic AMP / Q000032:analysis / Q000378:metabolism / Q000502:physiology*; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology*; D016762:Genes, fos / Q000235:genetics*; D016758:Genes, jun / Q000235:genetics*; D007328:Insulin / Q000235:genetics / Q000378:metabolism*; D007515:Islets of Langerhans / Q000737:chemistry / Q000166:cytology* / Q000378:metabolism*; D051379:Mice; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics / Q000378:metabolism
D000952:Antigens, Polyomavirus Transforming; D007328:Insulin; D012333:RNA, Messenger; D005576:Colforsin; D000242:Cyclic AMP; D015056:1-Methyl-3-isobutylxanthine