Abstract:
:Heat shock protein 70 (HSP70) inhibits apoptosis and thereby increases the survival of cells exposed to a wide range of lethal stimuli. HSP70 has also been shown to increase the tumorigenicity of cancer cells in rodent models. The protective function of this chaperone involves interaction and neutralization of the caspase activator apoptotic protease activation factor-1 and the mitochondrial flavoprotein apoptosis-inducing factor (AIF). In this work, we determined by deletional mutagenesis that a domain of AIF comprised between amino acids 150 and 228 is engaged in a molecular interaction with the substrate-binding domain of HSP70. Computer calculations favored this conclusion. On the basis of this information, we constructed an AIF-derived protein, which is cytosolic, noncytotoxic, yet maintains its capacity to interact with HSP70. This protein, designated ADD70, sensitized different human cancer cells to apoptosis induced by a variety of death stimuli by its capacity to interact with HSP70 and therefore to sequester HSP70. Thus, its chemosensitizing effect was lost in cells in which inducible HSP70 genes had been deleted. These data delineate a novel strategy for the selective neutralization of HSP70.
journal_name
Cancer Resjournal_title
Cancer researchauthors
Schmitt E,Parcellier A,Gurbuxani S,Cande C,Hammann A,Morales MC,Hunt CR,Dix DJ,Kroemer RT,Giordanetto F,Jäättelä M,Penninger JM,Pance A,Kroemer G,Garrido Csubject
Has Abstractpub_date
2003-12-01 00:00:00pages
8233-40issue
23eissn
0008-5472issn
1538-7445journal_volume
63pub_type
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