p53 function and metal levels in cancer cells

癌细胞中的 p53 功能和金属水平

• 批准号: 2743912
• 金额: --
• 依托单位: Durham University
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2743912
• 关键词: p53; function; metal; levels; cancer

This project is based on the observation that many cancers have metal overload and that increased metal levels are correlated to worse survival and increased chemoresistance. Many cancers have mutations in oncogenes and tumour suppressors and the most frequently occurring mutations are in the TP53 gene. These mutations can lead to loss of p53 expression or the expression of a mutated protein. Normal p53 prevents tumour formation by detecting DNA damage and either allowing for repair or for promoting apoptosis to prevent any damage from propagating to daughter cells. Mutated p53 can no longer fulfil these functions. More importantly mutant p53 also promotes spreading of the cancer and chemoresistance. In the Muller lab it was found that increased levels of those metals that accumulate in cancers can prevent p53 from functioning as tumour suppressor and actually make it behave as if it is a p53 that is mutated. In this project, we will design and a metal and p53 sensor to be able to correlate p53 activity to metal availability within cells. This will allow us to test chemosensitivity and test a variety of compounds that can impinge on these pathways in order to restore chemosensitivity.

该项目基于以下观察：许多癌症存在金属超载，并且金属水平增加与生存较差和化疗耐药性增加相关。许多癌症都存在癌基因和抑癌基因突变，最常见的突变发生在 TP53 基因中。这些突变可能导致 p53 表达缺失或突变蛋白表达。正常的 p53 通过检测 DNA 损伤并允许修复或促进细胞凋亡来防止任何损伤传播到子细胞，从而防止肿瘤形成。突变的 p53 不再能够履行这些功能。更重要的是，突变的p53还会促进癌症的扩散和化疗耐药性。 Muller 实验室发现，癌症中积累的金属水平增加可以阻止 p53 发挥肿瘤抑制因子的作用，实际上使其表现得就像是突变的 p53。在这个项目中，我们将设计一种金属和 p53 传感器，以便能够将 p53 活性与细胞内金属可用性相关联。这将使我们能够测试化学敏感性并测试各种可以影响这些途径的化合物，以恢复化学敏感性。