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Increased p21ras-specific Guanine-nucleotide exchange causes tumor-formation in nude-mice

R Zippel1, C Demaddalena, G Porro

  • 1CINISELLO BALSAMO,ITALFARMACO CTR RIC,MILAN,ITALY.

International Journal of Oncology
|May 14, 2011
PubMed

Insights

Guanine Nucleotide Releasing Proteins (GNRPs) like CDC25Mm can activate RAS proteins. This study shows that increased GNRP activity in cells correlates with tumor formation, suggesting their role in cancer development.

Area of Science:

  • Molecular Biology
  • Oncology
  • Cell Signaling

Background:

  • RAS proteins are key regulators of cell signaling, and their activation state is controlled by GTPase Activating Proteins (GAPs) and Guanine Nucleotide Releasing Proteins (GNRPs).
  • GNRPs, initially identified in yeast (CDC25, SDC25), have mammalian homologues with similar catalytic domains but distinct structures.
  • Dysregulation of RAS signaling pathways is frequently implicated in cancer development.

Purpose of the Study:

  • To investigate the function of the mammalian CDC25 homologue's catalytic domain in RAS signaling.
  • To determine if increased GNRP activity influences cellular transformation and tumor development.

Main Methods:

  • Cloning and expression of the C-terminal catalytic domain of a mouse CDC25 homologue (CDC25Mm) in fibroblasts.
  • Assay of p21ras-specific guanine nucleotide releasing activity in transfected cells.
  • In vivo assessment of the ras-responsive fos promoter activity.
  • Tumor induction studies in nude mice.

Main Results:

  • The catalytic domain of CDC25Mm was shown to transactivate the ras-responsive fos promoter in vivo.
  • Fibroblasts expressing the CDC25Mm catalytic domain exhibited increased p21ras-specific guanine nucleotide releasing activity.
  • This enhanced GNRP activity correlated with tumor induction in nude mice.

Conclusions:

  • The C-terminal catalytic domain of mouse CDC25Mm possesses GNRP activity.
  • Deregulation of mammalian GNRPs, such as CDC25Mm, may play a significant role in tumor development and cancer progression.
  • Targeting GNRPs could be a potential strategy for cancer therapy.

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