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

• Published in: Cell Vol. 79; no. 1; p. 81
• Main Authors: de Groot, R P, Ballou, L M, Sassone-Corsi, P
• Format: Journal Article
• Language: English
• Published: United States 07-10-1994
• Subjects: Amino Acid Sequence; Animals; Blood Proteins - pharmacology; Cell Line; Cyclic AMP Response Element Modulator; DNA - metabolism; DNA, Complementary; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Enzyme Activation - drug effects; Mitogens - pharmacology; Molecular Sequence Data; Phosphoproteins - analysis; Phosphorylation - drug effects; Polyenes - pharmacology; Protein Binding; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Recombinant Fusion Proteins - metabolism; Repressor Proteins; Ribosomal Protein S6 Kinases; Serine - metabolism; Sirolimus; Transcriptional Activation - drug effects; Transcriptional Activation - physiology; Transfection; Up-Regulation
• ISSN: 0092-8674
• DOI: 10.1016/0092-8674(94)90402-2

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.