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

受调控的细胞死亡对所有多细胞生物体的正常运作至关重要。被应激破坏的细胞可以选择主动参与内在的凋亡途径，从而导致它们的自我毁灭。处于压力下的细胞可以选择的另一种方法是抑制细胞的凋亡程序，并尝试修复损伤。这个决定在一定程度上是由分子伴侣热休克蛋白家族的成员决定的。这些蛋白质通过防止蛋白质的错误折叠和聚集来调节蛋白质的构象，并协助蛋白质向其天然状态的有效折叠。我实验室的工作重点是了解高温是如何触发细胞凋亡的，以及主要的热诱导蛋白Hsp70是如何阻止这种情况发生的。细胞死亡的过程是由线粒体细胞色素c和其他促凋亡因子的调节释放控制的。这一步骤受Bcl2家族促凋亡和抗凋亡蛋白的控制。我以前的工作已经证实，在淋巴样细胞中，热休克导致促凋亡的Bcl-2家族蛋白Bax从胞浆移位到线粒体，导致细胞色素c释放、凋亡体形成、caspase激活和细胞死亡。在Hsp70水平升高的细胞中，所有这些事件都被抑制。我们的数据表明，Hsp70主要作用于防止导致线粒体膜通透性的事件，从而控制死亡的决定，但不干扰该事件发生后细胞死亡的过程。这项提议的目的是确定(I)在热休克细胞中，只有BH3家族的哪些成员参与Bax的激活，以及(Ii)Hsp70如何破坏导致它们激活的信号。由于热休克蛋白的过度表达与肿瘤的发生有关，这些研究将更好地理解Hsp70对细胞凋亡的抑制是如何导致人类疾病的。

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.