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

Cell. 1994 Oct 7;79(1):81-91. doi: 10.1016/0092-8674(94)90402-2.

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 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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*

Substances

  • Blood Proteins
  • DNA, Complementary
  • DNA-Binding Proteins
  • Mitogens
  • Phosphoproteins
  • Polyenes
  • Recombinant Fusion Proteins
  • Repressor Proteins
  • Cyclic AMP Response Element Modulator
  • Serine
  • DNA
  • Protein-Serine-Threonine Kinases
  • Ribosomal Protein S6 Kinases
  • Sirolimus