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 ne rve 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 trigger s differentiation in these cells. We have tested this model by asking whether agents that stimulate MAP kinase without inducing differentiat ion can act additively to trigger differentiation. Neither forskolin n or epidermal growth factor can stimulate differentiation, yet both act ivate MAP kinase in these cells. Together, their actions on MAP kinase are synergistic. Cells treated with both agents differentiate, measur ed morphologically and by the induction of neural-specific genes. We p ropose that cellular responses to growth factor action are dependent n ot only on the activation of growth factor receptors by specific growt h factors but on synchronous signals that may elevate MAP kinase level s within the same cells.