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CHEMOSENSITIZATION BY A NON-APOPTOGENIC HEAT SHOCK PROTEIN 70-BINDING APOPTOSIS INDUCING FACTOR MUTANT
Citation:
Schmitt, E., A. Parcellier, S. Gurbuxani, C. Cande, A. Hammann, M. C. Morales, C. R. Hunt, D J. Dix, R. T. Kroemer, F. Giordanetto, M. Jaattela, J. M. Penniger, A. Pance, G. Kroemer, AND C. Garrido. CHEMOSENSITIZATION BY A NON-APOPTOGENIC HEAT SHOCK PROTEIN 70-BINDING APOPTOSIS INDUCING FACTOR MUTANT. CANCER RESEARCH 63(23):8233-8240, (2003).
Description:
Chemosensitization by a non-apoptogenic heat shock protein 70-binding apoptosis inducing factor mutant
Abstract
HSP70 inhibits apoptosis by neutralizing the caspase activator Apaf-1 and by interacting with apoptosis inducing factor (AIF), a mitochondrial flavoprotein which translocates upon apoptosis induction to the nucleus. Here we show that the only HSPs interacting with AIF belong to the HSP70 family. AIF inhibition by HSP70 involves a direct interaction with AIF, resulting in its cytosolic retention. Deletional mutagenesis of AIF revealed the existence of three domains involved in its apoptotic function : (i) a region (aa 150-228) which binds HSP70, (ii) a nuclear localization sequence (NLS) containing region (aa 367-459), and (iii) a C-terminal domain (aa 567-609) required for its chromatin-condensing activity. Based on this information, we deleted the MLS, the NLS, and the apoptogenic C-terminus to construct an AIF-derived protein which is cytosolic, non-cytotoxic, yet maintains its capacity to interact with HSP70. This protein, designated ADD70, sensitized different human cancer cells to apoptosis by its capacity to interact with 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.