Non-canonical functions of the apoptosis inhibitor Bcl-xL

描述（由申请人提供）：Bcl-2家族成员是程序性细胞死亡的调节因子，似乎在几种人类癌症中起因果作用。在细胞生命的最后几分钟，Bcl-2蛋白的功能是人们努力了解潜在分子细节的焦点。然而，Bcl-2蛋白在健康细胞中的功能很少被研究，尽管越来越多的证据表明它们有独特的“日常工作”，对正常的细胞过程至关重要。例如，我们已经证明抗凋亡的Bcl-2家族成员Bcl-xL调节线粒体形态、线粒体裂变和融合以及神经元中的突触活动，我们认为这将影响神经退行性变的初始步骤。然而，这种功能的分子机制尚不清楚，但与Bcl-2蛋白对细胞色素c释放的调节相比，它被认为是一种进化上更为保守的功能。细胞Bcl-2同源物也被预测会改变膜曲率。因此，Bcl-xL可能通过直接操纵脂质膜影响线粒体动力学。我建议确定Bcl-2家族蛋白是否直接参与膜结构的决定，是否参与膜融合反应。为了完成这项任务，我将使用定义的脂质和重组蛋白，以及细胞-细胞融合测定。

DESCRIPTION (provided by applicant): Bcl-2 family members are regulators of programmed cell death and appear to have causal roles in several human cancers. The functions of Bcl-2 proteins during the final minutes in a cell's life are the focus of intense effort to understand the underlying molecular details. However, the functions of Bcl-2 proteins in healthy cells are seldom investigated, despite increasing evidence that they have distinct "day jobs" that are crucial for normal cellular processes. For example, we have shown that the anti- apoptotic Bcl-2 family member, Bcl-xL, regulates mitochondrial morphology, mitochondrial fission and fusion, and synaptic activity in neurons, which we suggest will influence the initial steps in neurodegeneration. However, the molecular mechanism underlying this function is unknown, but is suggested to be a more evolutionarily conserved function of Bcl-2 proteins compared to their regulation of cytochrome c release. Cellular Bcl-2 homologues are also predicted to alter membrane curvature. Thus, Bcl-xL may influence mitochondrial dynamics by directly manipulating lipid membranes. I propose to determine if Bcl-2 family proteins have a direct role in membrane structure determination, and if they are involved in membrane fusion reactions. To accomplish this task, I will use defined lipids and recombinant proteins, as well as cell- cell fusion assays. PUBLIC HEALTH RELEVANCE: Bcl-xL and other Bcl-2 family members play a key role in promoting cancer progression and tumorigenesis by inhibiting apoptotic cell death. This is underscored by the development of small molecule inhibitors designed as anticancer agents that are currently in phase II/III clinical trials for the treatment of lymphoid malignancies, small- cell lung cancers and chronic lymphocytic leukemia. In addition, there is growing evidence that Bcl-2 modulate synaptic activity in healthy neurons by regulating mitochondrial membrane fusion/fission and mitochondrial localization, potentially influencing the initial steps in neurodegeneration. However, the biochemical function of these Bcl-2 family proteins that mediates these effects in neurons is essentially unknown and will be investigated here.