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，邻近活跃生长的细胞的副产物，感染病原体的副产物或结构成分，免疫系统的产物，制造蛋白质的过度需求以及对细胞或周围组织的损害。细胞通过激活特定的反应来做出反应，从而使它们能够应对这些应激源。虽然细胞应激反应对宿主有益，但它们也可能是有害的。例如，疱疹病毒已经进化成在宿主中保持潜伏，直到宿主受到压力。然后，他们利用这些反应中的一部分来感受压力并重新激活。此外，应激反应还允许癌细胞在低氧、辐射和抗癌药物的作用下存活并转移。在之前NSERC发现基金资助的一项提案中，我们发现了两种独特的细胞蛋白质，我们将其命名为鲁曼和张飞。这些蛋白在神经元中表达，并可能被单纯疱疹病毒用来决定是复制、潜伏还是重新激活。鲁曼和张飞的作用是相反的--鲁曼刺激病毒和宿主基因的表达，而张飞则抑制病毒和宿主的基因表达。自从他们发现以来，我们的实验室和其他人已经确定这两种蛋白质参与了广泛的重要生物学过程，包括调节应激反应，调节胰岛素的合成，允许树突状细胞(启动身体对病原体的反应的细胞)成熟，以及启动受损感觉神经元的修复。虽然很高兴看到我们的初步发现引起了如此多的兴趣，但我们仍然不知道陆曼和张飞是如何发挥他们的许多功能的。我们的建议就是试图确定这一点。至于Luman，我们将重点介绍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通路的测量相结合的方法来确定Luman是如何从损伤部位运输到细胞体的，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物的活性。

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.