POSITIVE REGULATION OF THE CAMP-RESPONSIVE ACTIVATOR CREM BY THE P70 S6 KINASE - AN ALTERNATIVE ROUTE TO MITOGEN-INDUCED GENE-EXPRESSION

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 (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.