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- Title
p53 mediated death of cells overexpressing MDM2 by an inhibitor of MDM2 interaction with p53.
- Authors
Wasylyk, Christine; Salvi, Roberto; Argentini, Manuela; Dureuil, Christine; Delumeau, Isabelle; Abecassis, Joseph; Debussche, Laurent; Wasylyk, Bohdan
- Abstract
The p53 tumour suppressor is frequently inactivated in human tumours. One form of inactivation results from overexpression of MDM2, that normally forms a negative auto-regulatory loop with p53 and inhibits its activity through complex formation. We have investigated whether disrupting the MDM2-p53 complex in cells that overexpress MDM2 is sufficient to trigger p53 mediated cell death. We find that expression of a peptide homologue of p53 that binds to MDM2 leads to increased p53 levels and transcriptional activity. The consequences are increased expression of the downstream effectors MDM2 and p21WAF1/CIP1, inhibition of colony formation, cell cycle arrest and cell death. There is also a decrease in E2F activity, that might have been due to the known physical and functional interactions of MDM2 with E2F1/DP1. However, this decrease is p53 dependent, as are also colony formation, cell cycle arrest and cell death. These results show that a peptide homologue of p53 is sufficient to induce p53 dependent cell death in cells overexpressing MDM2, and support the notion that disruption of the p53-MDM2 complex is a target for the development of therapeutic agents.
- Subjects
CELL cycle; APOPTOSIS; CELL death
- Publication
Oncogene, 1999, Vol 18, Issue 11, p1921
- ISSN
0950-9232
- Publication type
Article
- DOI
10.1038/sj.onc.1202528