Role of Siah proteins in inflammation and cancer

在这个项目中，我们的目标是确定Siah蛋白在肿瘤血管生成和炎症反应中的作用。缺氧，即氧张力的降低，限制了肿瘤的生长，在这些地方，氧气还没有通过新血管的形成而建立起来。此外，缺氧在炎症和伤口愈合的地方很常见，在那里血管被关闭以帮助恢复。通过使用我们的Siah基因敲除小鼠，我们有了一个独特的模型，使我们第一次能够研究Siah在缺氧信号级联中的作用。细胞对低氧水平的感知和反应是复杂的，涉及到几种蛋白质。其中一种关键蛋白被称为缺氧诱导因子（Hif-1）。它在缺氧条件下积累，并负责基因的表达，使细胞能够耐受和在缺氧条件下发挥作用。在缺氧条件下的耐受性和功能，这与新血管的形成有关。当氧气受限时，PHD蛋白指导Hif1的降解，而Siah则指导PHD的降解。Siah蛋白的缺失（例如在我们的敲除模型中）导致缺氧下PHD蛋白的增加，因此Hif-1不稳定，对缺氧的反应受损。因此，位于控制细胞内蛋白质分解（今年诺贝尔医学奖的焦点）的级联顶端的Siah主要控制对缺氧的反应。多细胞生物对获得性缺陷的相对免疫是通过冗余来实现的。氧是一个独特的例子，生物体不能通过冗余绕过缺陷，使其成为未来治疗的一个有吸引力的目标。因此，了解分子和细胞对缺氧的反应可能使我们能够确定开发新型抗炎和抗癌药物的关键分子。这项研究的范围是利用我们的敲除小鼠在炎症和癌症模型中了解Siah的关键作用。

In this project we aim to define the role of the Siah proteins in tumour angiogenesis and inflammatory responses. Hypoxia, a decrease in oxygen tension, places constrains on tumour growth where access to oxygen is yet to be established via new blood vessel formation. In addition hypoxia is common in areas of inflammation and wound healing, where blood vessels have been shut down to help in recovery. With the use of our Siah knockout mice we have a unique model that allows us, for the first time, to investigate the role of Siah in the hypoxia signalling cascade. How cells sense and react to low oxygen levels is complex and involves several proteins. A key protein is called Hypoxia induced factor, Hif-1. It accumulates under hypoxia and is responsible for the expression of genes enabling the cell to tolerate and function under hypoxic conditions. tolerate and function under hypoxic conditions, which is involved in new blood vessel formation. PHD protein directs the degradation of Hif1, while Siah directs the degradation of PHD, when oxygen is limiting. Loss of Siah proteins (eg in our knockout models) leads to an increase in PHD proteins under hypoxia thus no stabilisation of Hif-1 and impaired response to hypoxia. Thus, sitting on the top of a cascade, which controls the trashing of proteins in the cell (focus of this year's Nobel price for medicine), Siah has primary control on the response to oxygen deprivation. The relative immunity of multicellular organisms to acquired defects is through redundancy. Oxygen is a unique case, for which organisms can not bypass the defect via redundancy, making it an attractive target for future therapy. Therefore, understanding the molecular and cellular response to hypoxia may allow us to identify key molecules which could be targeted for the development of novel anti inflammatory and cancer drugs. The scope of this study is to understand the key role of Siah utilising our knockout mice in models of inflammation and cancer.