Regulation of stress-induced cell death by the molecular chaperone Hsp70

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Regulated cell death is essential for the proper functioning of all multicellular organisms. Cells that have been damaged by stress have the option of actively engaging the intrinsic apoptotic pathway leading to their self-destruction. Another option that is available to cells under stress is to suppress the apoptotic program and attempt to repair the damage. This decision is determined, in part, by members of the heat shock protein family of molecular chaperones. These proteins play essential roles in regulating protein conformation by preventing protein misfolding and aggregation as well as assisting in the productive folding of proteins to their native state. Work in my lab is focused on understanding how hyperthermia triggers apoptosis and how the major heat-inducible protein, Hsp70 prevents this from occurring. The process of cell death is controlled by the regulated release of cytochrome c and other proapoptotic factors from the mitochondria. This step is under the control of the Bcl-2 family of pro and anti-apoptotic proteins. My previous work has established that in lymphoid cells, heat shock causes the translocation of the pro-apoptotic Bcl-2 family protein Bax from the cytosol to the mitochondria leading to cytochrome c release, apoptosome formation, caspase activation and cell death. All of these events are inhibited in cells that have elevated levels of Hsp70. Our data suggests that Hsp70 primarily acts to prevent events leading up to mitochondrial membrane permeabilization and thereby controls the decision to die but does not interfere with the process of cell death after this event has occurred. The goals of this proposal are to determine (i) which of the BH3-only members of the Bcl-2 family are involved in the activation of Bax in heat-shocked cells and (ii) how Hsp70 disrupts the signal that leads to their activation. Since heat shock protein overexpression is associated with tumorigenesis, these studies will provide a better understanding of how the suppression of apoptosis by Hsp70 contributes to human disease.