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Mitogen-activated protein kinase phosphorylates and targets inducible cAMP early repressor to ubiquitin-mediated

G Yehia1, F Schlotter, R Razavi

  • 1Department of Obstetrics, Gynecology and Women's Health, New Jersey Medical School, Newark, New Jersey 07103, USA.

The Journal of Biological Chemistry
|July 24, 2001
PubMed

Insights

Cyclic AMP (cAMP) stabilizes the ICER protein by inhibiting the MAPK pathway, preventing its phosphorylation, ubiquitination, and degradation. This uncovers a novel signaling cross-talk mechanism regulating gene expression.

Area of Science:

  • Cellular signaling
  • Molecular biology
  • Cancer research

Background:

  • Inducible cAMP early repressor (ICER) mediates cAMP's antiproliferative effects and acts as a tumor suppressor.
  • Regulation of ICER protein stability is crucial for understanding its cellular functions.

Purpose of the Study:

  • To investigate the regulation of ICER protein stability by phosphorylation and ubiquitination.
  • To elucidate the interplay between cAMP and MAPK signaling pathways in controlling ICER levels.

Main Methods:

  • Experiments were conducted in human choriocarcinoma JEG-3 and mouse pituitary AtT20 cells.
  • Investigated ICER phosphorylation and ubiquitination in response to cAMP and MAPK pathway modulation.
  • Utilized a mutant ICER form (Ser-41 to alanine) to assess the role of specific phosphorylation sites.

Main Results:

  • cAMP stabilizes ICER by inhibiting the MAPK cascade, thereby reducing ICER phosphorylation.
  • Extracellular signal-regulated kinases 1 and 2 (MAPKs) directly phosphorylate ICER at Ser-41.
  • Phosphorylation at Ser-41 targets ICER for ubiquitination and proteasomal degradation; a non-phosphorylatable mutant exhibits increased stability.

Conclusions:

  • A novel cross-talk mechanism exists between MAPK and cAMP pathways in the nucleus.
  • MAPK signaling promotes ICER degradation via ubiquitination and proteasomal pathways.
  • This regulation impacts cAMP-dependent gene expression and ICER's role as a tumor suppressor.

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