A polymorphism in the Mdm2 promoter enhances cancer risk

描述(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，激活许多DNA损伤依赖的检查点反应和凋亡基因。编码P53抑制因子MDM2的基因在超过30%的肉瘤中被扩增，该蛋白在许多其他肿瘤中以未知的机制过度表达。因此，在绝大多数人类癌症中，P53途径在该途径中的多个点被失活。我们最近在人MDM2(MDM2)启动子中发现了一个单核苷酸多态性(SNP)，它创建了一个强大而稳定的Sp1结合位点，从而结构性地增加了MDM2的转录。这种从T到G的多态变化导致MDM2 mRNA和蛋白水平的增加，从而降低了P53的水平。这使得具有这种多态的个体更容易患癌症。我们相信，建立MDM2 SNP小鼠模型将使我们能够跟踪和直接观察这些小鼠肿瘤形成的自然渐进过程，从而更好地了解人类的这一复杂过程。

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.