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Inactivation of p53 signaling by p73 or PTEN ablation results in a transformed phenotype that remains susceptible to Nutlin-3 mediated apoptosis.

Abstract
The p53 signaling pathway is frequently disrupted in carcinogenesis. However, roughly 50% of all cancers express wild-type p53 and have alterations in accessory signaling components required for p53 activity. Using the well described E1A/RAS transformation model, in which p53 activity must be suppressed for transformation, we show here that p53 is inactive and unable to suppress transformation following ablation of p73 or PTEN. However, despite the transformed phenotype conferred by p53 inactivation following p73 or PTEN loss, p53 could be fully activated by Nutlin-3, resulting in efficient caspase-mediated apoptosis. Our novel and unexpected finding provides important information regarding the efficacy of Nutlin-3 and indicates that patients with tumors deficient in p53 function due to p73 or PTEN loss may benefit from Nutlin-3 treatment.
AuthorsRocky Cipriano, John T Patton, Lindsey D Mayo, Mark W Jackson
JournalCell cycle (Georgetown, Tex.) (Cell Cycle) Vol. 9 Issue 7 Pg. 1373-9 (Apr 01 2010) ISSN: 1551-4005 [Electronic] United States
PMID20305378 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References
  • DNA-Binding Proteins
  • Imidazoles
  • Nuclear Proteins
  • Piperazines
  • TP73 protein, human
  • Tumor Protein p73
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • nutlin 3
  • Proto-Oncogene Proteins c-mdm2
  • PTEN Phosphohydrolase
  • PTEN protein, human
Topics
  • Apoptosis (drug effects, genetics)
  • Blotting, Western
  • Cell Line
  • DNA-Binding Proteins (genetics, metabolism)
  • Humans
  • Imidazoles (pharmacology)
  • Nuclear Proteins (genetics, metabolism)
  • PTEN Phosphohydrolase (genetics, metabolism)
  • Piperazines (pharmacology)
  • Proto-Oncogene Proteins c-mdm2 (genetics, metabolism)
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tumor Protein p73
  • Tumor Suppressor Protein p53 (genetics, metabolism)
  • Tumor Suppressor Proteins (genetics, metabolism)

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