title: Wild-type and mutant p53 proteins interact with mitochondrial caspase-3.
abstract: Caspases play a key role in the apoptotic pathway by virtue of their ability to cleave key protein substrates within the dying cell. Caspases are produced as inactive zymogens, and need to become proteolytically processed in order to become active. A key executioner caspase, caspase-3, has previously been found to exist in both the cytosol and the mitochondria. At the mitochondria, caspase-3 is associated with both the inner and outer mitochondrial membranes, where it interacts with heat shock proteins Hsp60 and Hsp10. Like caspase-3, a small portion of the p53 tumor suppressor protein is localized to mitochondria, particularly after genotoxic stress. p53 interacts with various members of the Bcl2 family at the mitochondria, and this interaction is key to its ability to induce apoptosis. In this study, we sought to determine the identity of other mitochondrial p53-interacting proteins. Using immunoprecipitation from purified mitochondria followed by mass spectrometry we identified caspase-3 as a mitochondrial p53-interacting protein. Interestingly, we find that tumor-derived mutant forms of p53 retain the ability to interact with mitochondrial caspase-3. Further, we find evidence that these mutant forms of p53 may interfere with the ability of procaspase-3 to become proteolytically activated by caspase-9. The combined data suggest that tumor-derived mutants of p53 may be selected for in tumor cells due to their ability to bind and inhibit the activation of caspase-3.
authors.affiliation: Program in Developmental Therapeutics, Fox Chase Cancer Center, Philadelphia, PA, USA.
authors.forename: Amanda K
authors.initials: AK
authors.lastname: Frank
authors.forename: E Christine
authors.initials: EC
authors.lastname: Pietsch
authors.forename: Patrick
authors.initials: P
authors.lastname: Dumont
authors.forename: Joy
authors.initials: J
authors.lastname: Tao
authors.forename: Maureen E
authors.initials: ME
authors.lastname: Murphy
mesh_terms: D000595:Amino Acid Sequence; D053148:Caspase 3 / Q000378:metabolism*; D002460:Cell Line; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D021381:Protein Transport; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D050505:Mutant Proteins; D016159:Tumor Suppressor Protein p53; D053148:Caspase 3