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RESEARCH PRODUCT
Direct Activation of Bax by p53 Mediates Mitochondrial Membrane Permeabilization and Apoptosis
Tomomi KuwanaMartin SchulerNathalie DroinDonald D. NewmeyerDouglas R. GreenJerry E. ChipukLisa Bouchier-hayessubject
Tumor suppressor geneProtein ConformationUltraviolet RaysWheat Germ AgglutininsRecombinant Fusion Proteinsbcl-X ProteinApoptosisEndogenyMitochondrionBiologyPermeabilityHomology (biology)law.inventionMiceCytosollawProto-Oncogene ProteinsMitochondrial membrane permeabilizationAnimalsHumansCells CulturedCell Line Transformedbcl-2-Associated X ProteinCell NucleusMultidisciplinaryCytochromes cIntracellular MembranesGenes p53MitochondriaCell biologyCytosolGene Expression RegulationProto-Oncogene Proteins c-bcl-2ApoptosisLiposomesMutationSuppressorTumor Suppressor Protein p53biological phenomena cell phenomena and immunityCarrier ProteinsBH3 Interacting Domain Death Agonist ProteinHeLa Cellsdescription
The tumor suppressor p53 exerts its anti-neoplastic activity primarily through the induction of apoptosis. We found that cytosolic localization of endogenous wild-type or trans-activation–deficient p53 was necessary and sufficient for apoptosis. p53 directly activated the proapoptotic Bcl-2protein Bax in the absence of other proteins to permeabilize mitochondria and engage the apoptotic program. p53 also released both proapoptotic multidomain proteins and BH3-only proteins [Proapoptotic Bcl-2family proteins that share only the third Bcl-2homology domain (BH3)] that were sequestered by Bcl-xL. The transcription-independent activation of Bax by p53 occurred with similar kinetics and concentrations to those produced by activated Bid. We propose that when p53 accumulates in the cytosol, it can function analogously to the BH3-only subset of proapoptotic Bcl-2proteins to activate Bax and trigger apoptosis.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2004-02-14 | Science |