Role of Siah proteins in inflammation and cancer

Siah 蛋白在炎症和癌症中的作用

• 批准号: nhmrc : 400321
• 负责人: A/Pr Andreas Moeller
• 金额: $ 33.82万
• 依托单位: The University of Melbourne
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2006
• 资助国家: 澳大利亚
• 起止时间: 2006-01-01 至 2008-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/role-siah-proteins-inflammation-cancer/98760
• 关键词: Role; Siah; proteins; inflammation; cancer

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.

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，会限制肿瘤的生长，因为肿瘤的生长尚未通过新血管的形成来获得氧气。此外，缺氧在炎症和伤口愈合区域很常见，这些区域的血管被关闭以帮助恢复。通过使用 Siah 基因敲除小鼠，我们拥有了一个独特的模型，使我们能够首次研究 Siah 在缺氧信号级联中的作用。细胞如何感知低氧水平并做出反应是复杂的，涉及多种蛋白质。一种关键蛋白质称为缺氧诱导因子 Hif-1。它在缺氧条件下积累，负责基因的表达，使细胞能够在缺氧条件下耐受并发挥作用。在缺氧条件下耐受并发挥作用，这涉及新血管的形成。当氧气有限时，PHD 蛋白指导 Hif1 的降解，而 Siah 指导 PHD 的降解。 Siah 蛋白的缺失（例如在我们的敲除模型中）会导致缺氧下 PHD 蛋白增加，因此 Hif-1 不会稳定，并且对缺氧的反应受损。因此，坐在级联的顶部，控制细胞中蛋白质的废弃（今年诺贝尔医学奖的焦点），西亚对缺氧反应具有主要控制作用。多细胞生物体对获得性缺陷的相对免疫力是通过冗余实现的。氧气是一种独特的情况，生物体无法通过冗余来绕过缺陷，这使其成为未来治疗的有吸引力的目标。因此，了解对缺氧的分子和细胞反应可能使我们能够识别出可用于开发新型抗炎和癌症药物的关键分子。本研究的范围是了解 Siah 利用我们的基因敲除小鼠在炎症和癌症模型中的关键作用。