Non-canonical functions of the apoptosis inhibitor Bcl-xL

描述(申请人提供)：BCL-2家族成员是程序性细胞死亡的调节者，似乎在几种人类癌症中起到了因果作用。在细胞生命的最后几分钟，为了了解潜在的分子细节，Bcl-2蛋白的功能是人们密切关注的焦点。然而，尽管越来越多的证据表明，在正常的细胞过程中，它们有不同的“日常工作”，但很少有人研究健康细胞中的Bcl-2蛋白的功能。例如，我们已经证明了抗凋亡的Bcl2家族成员，Bclxl，调节神经元中线粒体的形态，线粒体的分裂和融合，以及突触活动，我们认为这将影响神经退化的初始步骤。然而，这一功能背后的分子机制尚不清楚，但与其对细胞色素c释放的调节相比，Bcl2蛋白可能是一种进化上更保守的功能。细胞内的Bcl2同源基因也被预测可以改变细胞膜的曲率。因此，Bclxl可能通过直接操纵脂质膜来影响线粒体的动力学。我建议确定Bcl-2家族蛋白是否在膜结构确定中起直接作用，以及它们是否参与膜融合反应。为了完成这项任务，我将使用定义的脂类和重组蛋白，以及细胞-细胞融合分析。 公共卫生相关性：bclxl和其他bcl2家族成员通过抑制凋亡细胞死亡，在促进癌症进展和肿瘤发生方面发挥关键作用。作为抗癌剂的小分子抑制剂的开发突显了这一点，目前这些药物正处于治疗淋巴系恶性肿瘤、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的突触活性，从而潜在地影响神经退变的初始步骤。然而，这些在神经元中介导这些效应的Bcl-2家族蛋白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.