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Cell. 1994 Oct 7;79(1):81-91.

Positive regulation of the cAMP-responsive activator CREM by the p70 S6 kinase: an alternative route to mitogen-induced gene expression.

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Laboratoire de Génétique Moléculaire des Eucaryotes, Centre National de la Recherche Scientifique, Faculté de Médecine, Strasbourg, France.


Activation of the adenylyl cyclase signaling pathway elicits the induction of genes via activators binding to cAMP-responsive elements (CREs). Nuclear factor CRE modulator (CREM) is activated by PKA-mediated phosphorylation on a serine at position 117. We show that Ser-117 is also phosphorylated by the mitogen-activated p70 S6 kinase (p70S6K) in vitro. Activation of cellular p70S6K by serum factors enhances Ser-117 phosphorylation and CREM transactivation. Coexpression of p70S6K significantly increases transactivation by a GAL4-CREM fusion. The macrolide rapamycin, a potent and specific inhibitor of p70S6K in vivo, completely blocks CREM activation induced by serum and by p70S6K. Thus, CREM constitutes a target for mitogenic signaling through p70S6K and may acts as a nuclear effector in which transduction pathways may converge and cross-talk.

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