Role of Luman/CREB3 and Zhangfei/CREBZF in cellular stress responses and neuronal regeneration

细胞受到压力的原因有很多：缺乏氧气或营养，邻近活跃生长细胞的副产品，感染病原体的副产品或结构成分，免疫系统的产物，对蛋白质的过度需求以及对细胞或周围组织的损害。细胞通过激活专门的反应来科普这些压力。虽然细胞应激反应是为了使宿主受益，但它们也可能是有害的。例如，疱疹病毒已经进化到在宿主体内保持潜伏状态，直到宿主受到压力。然后，他们利用这些反应中的一些来感知压力并重新激活。此外，应激反应也使癌细胞能够在缺氧、辐射和抗癌药物中存活并转移。在之前的NSERC发现基金资助的提案中，我们发现了两种独特的细胞蛋白质，我们将其命名为Luman和Zhangfei。这些蛋白质在神经元中表达，并可能被单纯疱疹病毒用来决定是否复制，潜伏或重新激活。鲁曼蛋白和张飞蛋白的作用是相互交叉的--鲁曼蛋白刺激病毒和宿主基因的表达，而张飞蛋白则抑制病毒和宿主基因的表达。自从他们被发现以来，我们的实验室和其他人已经确定这两种蛋白参与了多种重要的生物学过程，包括调节应激反应，调节胰岛素的合成，使树突状细胞（启动机体对病原体反应的细胞）成熟并启动受损感觉神经元的修复。虽然令人欣慰的是，我们最初的发现引起了如此多的兴趣，我们仍然不知道鲁曼和张飞如何执行他们的许多功能。我们的建议就是试图确定这一点。关于Luman，我们将重点关注它在受损神经元恢复中的作用。我们将使用活细胞显微镜和基因表达，蛋白激酶和细胞内信号传导途径的测量相结合，以确定如何从损伤部位运输到细胞体，以及当它到达那里时它会做什么。我们还将研究张飞如何能够抑制介导应激反应和癌细胞生长的基因激活剂的活性。

Cells can be stressed for many reasons: lack of oxygen or nutrients, by-products of neighbouring actively growing cells, by products or structural components of infecting pathogens, products of the immune system, excessive demands to make protein and damage to the cell or surrounding tissue. Cells react by activating specialized responses that allow them to cope with these stressors. While cellular stress responses are meant to benefit the host, they can be detrimental as well. For instance, herpesviruses have evolved to remain latent in their hosts until their host is stressed. They then exploit some of these responses to sense stress and reactivate. In addition, stress responses also allow cancer cells to survive hypoxia, radiation and anti-cancer drugs and to metastasize. In a previous NSERC-Discovery grant funded proposal we discovered two unique cellular proteins which we named Luman and Zhangfei. These proteins are expressed in neurons and may be used by herpes simplex virus to decide whether to replicate, become latent or reactivate. Luman and Zhangfei act at cross-purposes - Luman stimulates viral and host gene expression while Zhangfei suppresses it. Since their discovery, our laboratory and others have determined that the two proteins are involved in a wide variety of important biological processes including modulating stress responses, regulating the synthesis of insulin, allowing dendritic cells (cells that initiate the body's response to pathogens) to mature and initiating the repair of injured sensory neurons. While it is gratifying to see that our initial discovery has generated so much interest, we still do not know how Luman and Zhangfei perform their many functions. Our proposal is an attempt to determine this. Regarding Luman, we will focus on its role in the recovery of the injured neuron. We will use a combination of live-cell microscopy and measurement of gene expression, protein kinases and intracellular signalling pathways to determine how Luman is transported from the site of injury to the cell body and what it does when it gets there. We will also study how Zhangfei is able to suppress the activity of gene activators that mediate stress responses and cancer cell growth.