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 serlne at position 117. We show that Ser-117 is also phosphorylated by the mitogenactivated p70 S6 kinase (~ 70~~) in vitro. Activation of cellular p70SeK by serum factors enhances Ser-117 phosphorylation and CREM transactivation. Coexpression of p70m significantly increases transactivation by a GAL4-CREM fusion. The macrolide rapamycin, a potent and specific inhibitor of~ 70~ in vivo, completely blocks CREM activation induced by serum and by~ 70~~. Thus, CREM constitutes a target for mitogenie signaling through~ 70~ and may acts as a nuclear effector in which transduction pathways may converge and cross-talk.