Multiple synergistic signal transduction pathways regulate c-fos expression in Swiss 3T3 cells: the role of cyclic AMP.
The promoter region of the c-fos gene contains several upstream enhancer elements which dictate the transcriptional response to specific intracellular signals. Among these is the cyclic AMP (cAMP)-responsive element, which is required for c-fos expression by cAMP in vitro. However, we have previously shown that cAMP-elevating agents cause only a slight increase in c-fos mRNA levels in intact Swiss 3T3 cells. Here, we show that cAMP can potentiate the induction of c-fos by other second messengers. A combination of forskolin and either phorbol-12,13-dibutyrate or epidermal growth factor leads to an increase in c-fos mRNA levels comparable to those induced by bombesin or serum. Furthermore, cAMP-elevating agents can act in synergy with calcium ionophores (which alone do not induce c-fos) to increase c-fos expression by up to 60% of the bombesin response, although, in parallel cultures, this combination does not stimulate the phosphorylation of 80K, an Mr 80,000 protein, which is a major substrate for protein kinase C. These results suggest that, in intact cells, cAMP acts synergistically with distinct intracellular signals to stimulate c-fos transcription through protein kinase C-dependent and -independent pathways.
Mehmet
H
H
Growth Regulation Laboratory, Imperial Cancer Research Fund, London, United Kingdom.
Morris
C
C
Rozengurt
E
E
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000818:Animals; D001839:Bombesin / Q000494:pharmacology; D000001:Calcimycin / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000502:physiology*; D004789:Enzyme Activation / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D051379:Mice; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis*; D016760:Proto-Oncogene Proteins c-fos; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis; D015398:Signal Transduction / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects
D011518:Proto-Oncogene Proteins; D016760:Proto-Oncogene Proteins c-fos; D016271:Proto-Oncogene Proteins c-myc; D005576:Colforsin; D015240:Phorbol 12,13-Dibutyrate; D000001:Calcimycin; D004815:Epidermal Growth Factor; D000242:Cyclic AMP; D011493:Protein Kinase C; D001839:Bombesin; D015056:1-Methyl-3-isobutylxanthine