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Essential role of p38gamma in K-Ras transformation independent of phosphorylation

Jun Tang1, Xiaomei Qi, Dan Mercola

  • 1Department of Radiation Oncology, Loyola University of Chicago, Maywood, Illinois 60153, USA.

The Journal of Biological Chemistry
|April 27, 2005
PubMed

Insights

K-Ras activates p38gamma, promoting colon cancer growth independently of phosphorylation. This p38gamma protein is found in K-ras-mutated colon cancer cells and may be a new target for cancer therapy.

Area of Science:

  • Cellular signaling pathways
  • Oncogene research
  • Cancer biology

Background:

  • Mitogen-activated protein kinase (MAPK) cascades regulate Ras oncogene activity.
  • ERK MAPK pathway is essential for Ras transformation.
  • p38 MAPK activity previously shown to inhibit Ras signaling in cancer cells.

Purpose of the Study:

  • Investigate the role of p38gamma, a p38 MAPK family member, in K-Ras-driven transformation.
  • Determine the mechanism by which p38gamma influences Ras signaling.
  • Evaluate p38gamma as a potential diagnostic marker and therapeutic target for colon cancer.

Main Methods:

  • Studied K-Ras activation of p38gamma in rat intestinal epithelial cells.
  • Depleted p38gamma to assess its effect on Ras transformation.
  • Analyzed p38gamma complex formation with ERK proteins.
  • Examined p38gamma expression in human colon cancer tissues.

Main Results:

  • K-Ras activated p38gamma by inducing its expression, not phosphorylation.
  • Depletion of p38gamma suppressed Ras transformation.
  • Unphosphorylated p38gamma promoted Ras transformation via increased complex formation with ERK.
  • Functional p38gamma was expressed in K-ras-mutated colon cancer cells, with increased transcripts in primary tumors.

Conclusions:

  • p38gamma plays a critical, phosphorylation-independent role in K-Ras transformation.
  • Elevated p38gamma is a potential diagnostic marker for human colon cancer.
  • p38gamma represents a novel therapeutic target for K-Ras-mutated colon cancers.

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