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Bypass of abnormal MDM2 inhibition of p53-dependent growth suppression

R D Meng1, H Shih, N S Prabhu

  • 1Laboratory of Molecular Oncology and Cell Cycle Regulation, University of Pennsylvania School of Medicine, Philadelphia 19104, USA.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|May 14, 1998
PubMed

Insights

MDM2 oncoprotein hinders p53

Area of Science:

  • Oncology
  • Molecular Biology
  • Gene Therapy

Background:

  • MDM2 oncoprotein inhibits p53-dependent cell cycle arrest and apoptosis.
  • MDM2 overexpression confers resistance to p53-based gene therapy in cancer cells.

Purpose of the Study:

  • To investigate if p21 can bypass MDM2-mediated resistance to p53.
  • To determine if Rb phosphorylation state predicts response to Ad-p53 or Ad-p21 gene therapy.

Main Methods:

  • In vitro studies using MDM2-overexpressing and low MDM2-expressing human cancer cell lines.
  • Infection with p53-expressing adenovirus (Ad-p53) and p21-expressing adenovirus (Ad-p21).
  • Assessment of tumor growth inhibition, cell morphology, and Rb phosphorylation state.

Main Results:

  • MDM2-overexpressing cells were resistant to Ad-p53 but sensitive to Ad-p21.
  • The cyclin-dependent kinase-inhibitory region of p21 was sufficient to overcome MDM2-p53 feedback loop.
  • Rb phosphorylation state correlated with treatment response; Ad-p21 induced quiescent large-cell morphology.

Conclusions:

  • p21 can effectively bypass MDM2-mediated resistance to p53 in cancer.
  • Rb phosphorylation status may serve as a predictive biomarker for Ad-p53 or Ad-p21 gene therapy outcomes.

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