A polymorphism in the Mdm2 promoter enhances cancer risk

Mdm2 启动子的多态性会增加癌症风险

• 批准号: 7156472
• 负责人: Sean M Post
• 金额: $ 5.04万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-20 至 2007-08-19
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7156472
• 关键词: cancer risk; human; neoplasm /cancer; proteins

DESCRIPTION (provided by applicant): One of the most commonly inactivated pathways in human cancers is the p53 tumor suppressor pathway. The p53 gene encodes a transcription factor required for the activation of numerous DNA-damage dependent checkpoint response and apoptotic genes.The gene encoding Mdm2, a p53 inhibitor, is amplified in over 30% of sarcomas and the protein is overexpressed by unknown mechanisms in many other tumors. Thus, the p53 pathway is inactivated in the vast majority of human cancers at multiple points within this pathway. We have recently identified a single nucleotide polymorphism (SNP) in the human Mdm2 (MDM2) promoter that creates a strong and stable Sp1 binding site that constitutively increases MDM2 transcription. This polymorphic change, a T to G, results in increased MDM2 mRNA and protein levels and consequently decreased p53 levels. This renders individuals with this polymorphism more susceptible to cancer. We believe that generating an Mdm2 SNP mouse model will allow us to follow and directly observe the stepwise natural progression of tumorigenesis in these mice and therefore have a better understanding of this complex process in humans.

描述（由申请人提供）：人类癌症中最常见的失活途径之一是p53肿瘤抑制途径。p53基因编码一种转录因子，该转录因子激活许多DNA损伤依赖性检查点反应和凋亡基因，编码P53抑制剂Mdm 2的基因在超过30%的肉瘤中扩增，并且该蛋白在许多其他肿瘤中通过未知机制过表达。因此，在绝大多数人类癌症中，p53通路在该通路内的多个点处失活。我们最近在人类MDM2（MDM2）启动子中发现了一个单核苷酸多态性（SNP），该多态性产生了一个强大而稳定的Sp1结合位点，可组成性地增加MDM2的转录。这种多态性变化，T到G，导致MDM2 mRNA和蛋白水平增加，从而降低p53水平。这使得具有这种多态性的个体更容易患癌症。我们相信，生成Mdm 2 SNP小鼠模型将使我们能够跟踪并直接观察这些小鼠中肿瘤发生的逐步自然进展，从而更好地了解人类的这一复杂过程。