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具有因果作用。Bcl-2蛋白在细胞生命的最后几分钟的功能是理解潜在分子细节的重点。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具有对正常细胞过程至关重要的独特的“日常工作”。例如，我们已经表明，抗凋亡Bcl-2家族成员Bcl-xL调节神经元中的线粒体形态、线粒体分裂和融合以及突触活性，我们认为这将影响神经变性的初始步骤。然而，这种功能的分子机制是未知的，但建议是一个更进化保守的Bcl-2蛋白的功能相比，他们的细胞色素c释放的调节。细胞Bcl-2同源物也被预测改变膜曲率。因此，Bcl-xL可能通过直接操纵脂质膜来影响线粒体动力学。 我建议确定Bcl-2家族蛋白是否在膜结构测定中具有直接作用，以及它们是否参与膜融合反应。为了完成这项任务，我将使用确定的脂质和重组蛋白，以及细胞-细胞融合试验。 公共卫生相关性：Bcl-xL和其他Bcl-2家族成员通过抑制凋亡性细胞死亡在促进癌症进展和肿瘤发生中起关键作用。这一点通过设计为抗癌剂的小分子抑制剂的开发得到强调，所述小分子抑制剂目前处于用于治疗淋巴恶性肿瘤、小细胞肺癌和慢性淋巴细胞白血病的II/III期临床试验中。此外，越来越多的证据表明Bcl-2通过调节线粒体膜融合/分裂和线粒体定位来调节健康神经元中的突触活性，从而潜在地影响神经变性的初始步骤。然而，这些Bcl-2家族蛋白介导神经元中这些效应的生化功能基本上是未知的，将在这里进行研究。

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.