Cyclic adenosine monophosphate can convert epidermal growth factor into a differentiating factor in neuronal cells.
The rat pheochromocytoma (PC12) cell line is a model for studying the mechanism of growth factor action. Both epidermal growth factor and nerve growth factor stimulate mitogen-activated protein (MAP) kinase in these cells. Recent data suggest that the transient activation of MAP kinase may trigger proliferation, whereas sustained activation triggers differentiation in these cells. We have tested this model by asking whether agents that stimulate MAP kinase without inducing differentiation can act additively to trigger differentiation. Neither forskolin nor epidermal growth factor can stimulate differentiation, yet both activate MAP kinase in these cells. Together, their actions on MAP kinase are synergistic. Cells treated with both agents differentiate, measured morphologically and by the induction of neural-specific genes. We propose that cellular responses to growth factor action are dependent not only on the activation of growth factor receptors by specific growth factors but on synchronous signals that may elevate MAP kinase levels within the same cells.
Yao
H
H
Department of Microbiology and Immunology, Oregon Health Sciences University, Portland 97201, USA.
Labudda
K
K
Rim
C
C
Capodieci
P
P
Loda
M
M
Stork
P J
PJ
D000310:Adrenal Gland Neoplasms; D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000096:biosynthesis / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D015500:Chloramphenicol O-Acetyltransferase / Q000096:biosynthesis / Q000378:metabolism; D005576:Colforsin / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism*; D004347:Drug Interactions; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D007700:Kinetics; D019278:Matrix Metalloproteinase 3; D008666:Metalloendopeptidases / Q000096:biosynthesis / Q000235:genetics; D048052:Mitogen-Activated Protein Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D009414:Nerve Growth Factors / Q000494:pharmacology; D009474:Neurons / Q000166:cytology* / Q000187:drug effects; D016716:PC12 Cells; D010673:Pheochromocytoma; D011401:Promoter Regions, Genetic; D011494:Protein Kinases / Q000096:biosynthesis / Q000378:metabolism*; D051381:Rats; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection
D009363:Neoplasm Proteins; D009414:Nerve Growth Factors; D011994:Recombinant Proteins; D005576:Colforsin; D004815:Epidermal Growth Factor; D000242:Cyclic AMP; D015500:Chloramphenicol O-Acetyltransferase; D011494:Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D008666:Metalloendopeptidases; D019278:Matrix Metalloproteinase 3