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

Abstract

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 mitogenactivated p70 S6 kinase (p70 S6K) in vitro. Activation of cellular p70 S6K by serum factors enhances Ser-117 phosphorylation and CREM transactivation. Coexpression of p70 S6K significantly increases transactivation by a GAL4-CREM fusion. The macrolide rapamycin, a potent and specific inhibitor of p70 S6K in vivo, completely blocks CREM activation induced by serum and by p70 S6K. Thus, CREM constitutes a target for mitogenic signaling through p70 S6K and may acts as a nuclear effector in which transduction pathways may converge and cross-talk.