cAMP abrogates the p21ras-mitogen-activated protein kinase pathway in fibroblasts.
The mechanism by which cAMP inhibits growth factor-induced DNA synthesis in fibroblasts is not understood. Here we show that in Rat-1 fibroblasts, cAMP-raising agents inhibit p21ras-mediated mitogen-activated protein (MAP) kinase activation induced by either epidermal growth factor or lysophosphatidic acid. Under the same conditions, however, epidermal growth factor- or lysophosphatidic acid-induced protein tyrosine phosphorylation, Ca2+ mobilization, and activation of Na+/H+ exchange are not attenuated. In ras-transformed Rat-1 cells, 8-bromo-cAMP rapidly deactivates constitutively active MAP kinase without reducing p21ras.GTP levels; long term 8-bromo-cAMP treatment of these cells leads to growth arrest and reversion of the transformed phenotype. These results show that elevation of intracellular cAMP levels abrogates the p21ras MAP kinase pathway at a step downstream of p21ras activation. This finding provides a molecular basis for the growth-inhibitory action of cAMP in normal and transformed fibroblasts.
Hordijk
P L
PL
Division of Cellular Biochemistry, Netherlands Cancer Institute, Amsterdam.
Verlaan
I
I
Jalink
K
K
van Corven
E J
EJ
Moolenaar
W H
WH
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002772:Cholera Toxin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D004247:DNA / Q000096:biosynthesis* / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D007545:Isoproterenol / Q000494:pharmacology; D007700:Kinetics; D008246:Lysophospholipids / Q000494:pharmacology; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism*; D051381:Rats; D013936:Thymidine / Q000494:pharmacology
D008246:Lysophospholipids; D015124:8-Bromo Cyclic Adenosine Monophosphate; D004815:Epidermal Growth Factor; D004247:DNA; D002772:Cholera Toxin; D000242:Cyclic AMP; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D016283:Proto-Oncogene Proteins p21(ras); D007545:Isoproterenol; D002118:Calcium; D015056:1-Methyl-3-isobutylxanthine; D013936:Thymidine