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RESEARCH PRODUCT
Pharmacologic activation of p53 elicits Bax-dependent apoptosis in the absence of transcription
Jerry E. ChipukDouglas R. GreenMartin SchulerUlrich Maurersubject
Cancer ResearchTranscription GeneticRecombinant Fusion ProteinsMutantEstrogen receptorApoptosis03 medical and health sciencesMice0302 clinical medicineBcl-2-associated X proteinProto-Oncogene ProteinsTumor Cells CulturedAnimalsHumansCloning MolecularReceptorCells Cultured030304 developmental biologybcl-2-Associated X ProteinCell NucleusProtein Synthesis Inhibitors0303 health sciencesAza CompoundsbiologyCytochrome cCytochromes cCell BiologyFibroblastsBridged Bicyclo Compounds Heterocyclic3. Good healthCell biologyTransport proteinMitochondriaProtein TransportTamoxifenProto-Oncogene Proteins c-bcl-2Receptors EstrogenOncologyApoptosis030220 oncology & carcinogenesisMutationbiology.proteinTumor Suppressor Protein p53Binding domaindescription
AbstractRecent efforts to develop pharmacologic agents that restore function to mutant forms of p53 hold significant promise in cancer therapy. Here, we examine the effects of such pharmacologic activation of p53 function using a small molecule, PRIMA-1, and a model system employing a p53 protein fused to a mutant steroid binding domain of the murine estrogen receptor (p53ERtam) that renders it responsive only in the presence of 4-hydroxytamoxifen. In either case, p53 activation triggered apoptosis that was not inhibited by the presence of macromolecular synthesis inhibitors. This p53-induced, transcription-independent apoptosis is Bax dependent, proceeds in the absence of a nucleus, and involves Bax translocation and cytochrome c release. Hence, pharmacologic p53 modulators can activate a transcription-independent apoptotic program.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2003-11-01 | Cancer Cell |