Mechanism of heat-induced cell death and its regulation by the molecular chaperone protein Hsp70

点击翻译按钮获取中文摘要

Cells respond to stressful stimuli by activating an evolutionarily conserved 'heat shock response' that results in the increased production of heat shock proteins. These proteins are part of a defense mechanism that acts to limit the extent of protein damage and thereby allows cells and organisms to survive temperature stresses that would normally be lethal. The heat shock proteins function as molecular chaperones in that they assist in protein folding, which is disrupted by elevated temperature exposure as well as other protein-damaging stresses. Stress-induced cell death occurs through a regulated process of cell elimination known as apoptosis. We have demonstrated that the major heat-shock protein, Hsp70 prevents stress-induced apoptosis. The long-term goal of my research program is to determine how hyperthermia triggers apoptosis and how the major heat-inducible protein, Hsp70, prevents this from occurring. My hypothesis is that heat stress affects the activity of specific Bcl-2 family proteins, which are central to the regulation of apoptosis. The objectives of this proposal are to determine the effect of hyperthermia on the expression, stability, post-translational modifications and interaction partners of the pro-apoptotic Bcl-2 family protein Noxa. An additional and related goal is to determine the nature of the heat-sensitive target that leads to the activation of stress-induced apoptosis. Specifically, we will (i) determine the role of phosphorylation in the control of Noxa protein levels and its interaction with the anti-apoptotic Bcl-2 family protein Mcl-1, (ii) determine the mechanism controlling heat-induced Noxa mRNA accumulation by examining the role of microRNAs in the regulation of Noxa mRNA transcript levels and (iii) determine whether the pro-apoptotic Bcl-2 family protein Bax is directly activated by temperature elevation by examining the temperature activation profile of human Bax protein expressed in the cells of a cold-blooded vertebrate (frogs). The work will advance our understanding of how cell stress triggers apoptosis and how this is suppressed by Hsp70. These studies will therefore provide insight into the fundamental ability of cells and organisms to adapt and persist in stressful environments.