Volume 271, Number 23, Issue of June 7, 1996 pp. 13476-13483
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

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cAMP-mediated Growth Inhibition in Fibroblasts Is Not Mediated via Mitogen-activated Protein (MAP) Kinase (ERK) Inhibition
cAMP-DEPENDENT PROTEIN KINASE INDUCES A TEMPORAL SHIFT IN GROWTH FACTOR-STIMULATED MAP KINASES

(Received for publication, February 22, 1996, and in revised form, March 22, 1996)

From the Centre de Biochimie, CNRS, Parc Valrose, 06108 Nice, France

Growth factors stimulate fibroblast cell division by activating the recently identified mitogen-activated protein kinase (MAP kinase) signaling cascade. In contrast to our previous work (Kahan, K., Seuwen, K., Meloche, S. and Pouysségur, J. (1992) J. Biol. Chem. 267, 13369-13375), several reports have suggested that an elevation in intracellular cAMP blocks cell proliferation by attenuating MAP kinase activation. Hence we re-examined the effect of a long term increase in intracellular cAMP and therefore cAMP-dependent protein kinase (PKA) activation on the MAP kinase cascade in CCL39 fibroblasts. The concomitant addition of cAMP-elevating agents prostaglandin E, (PGE₁) and IBMX did not inhibit the mitogen-mediated activation of p44 MAP kinase. However, a 5-min PGE₁/IBMX pretreatment abolished the MAP kinase response, in a manner correlating with the extent of PKA activity. This inhibition was temporal in nature, and while modifying the time course of growth factor-mediated p44 MAP kinase, activation did not diminish the magnitude of the response. Thus the major peak of MAP kinase activity normally present 5 min after -thrombin addition was now evident at 10 min in the presence of PGE₁/IBMX. CCL39 cell proliferation is inhibited by elevated cAMP levels. Such an inhibition could reflect either a reduction in the number of cells entering the cell cycle or a delay in the time required to go through the cycle. Bromodeoxyuridine labeling experiments revealed that the cAMP-mediated inhibition of DNA synthesis in CCL39 cells was not due to a delay in S phase entry, but was due to a reduction in the number of cells entering S phase.

Thus we conclude that although PKA activation may slightly modify the time course of MAP kinase activation in response to mitogens in CCL39 cells, the PKA-mediated inhibition of cell division occurs through modulation of an intracellular target, distinct from the p42/p44 MAP kinase cascade.

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