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 (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.
de Groot
R P
RP
Laboratoire de Génétique Moléculaire des Eucaryotes, Centre National de la Recherche Scientifique, Faculté de Médecine, Strasbourg, France.
Ballou
L M
LM
Sassone-Corsi
P
P
D000595:Amino Acid Sequence; D000818:Animals; D001798:Blood Proteins / Q000494:pharmacology; D002460:Cell Line; D051786:Cyclic AMP Response Element Modulator; D004247:DNA / Q000378:metabolism; D018076:DNA, Complementary; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D008934:Mitogens / Q000494:pharmacology; D008969:Molecular Sequence Data; D010750:Phosphoproteins / Q000032:analysis; D010766:Phosphorylation / Q000187:drug effects; D011090:Polyenes / Q000494:pharmacology; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012097:Repressor Proteins; D019893:Ribosomal Protein S6 Kinases; D012694:Serine / Q000378:metabolism; D020123:Sirolimus; D015533:Transcriptional Activation / Q000187:drug effects / Q000502:physiology*; D014162:Transfection; D015854:Up-Regulation
D001798:Blood Proteins; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D008934:Mitogens; D010750:Phosphoproteins; D011090:Polyenes; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D051786:Cyclic AMP Response Element Modulator; D012694:Serine; D004247:DNA; D017346:Protein Serine-Threonine Kinases; D019893:Ribosomal Protein S6 Kinases; D020123:Sirolimus