A single nucleotide polymorphism in the MDM2 promoter attenuates the p53 tumor suppressor pathway and accelerates tumor formation in humans

The tumor suppressor p53 gene is mutated in minimally half of all cancers. It is therefore reasonable to assume that naturally occurring polymorphic genetic variants in the p53 stress response pathway might determine an individual's susceptibility to cancer. A central node in the p53 pathway is the MDM2 protein, a direct negative regulator of p53. In this report, a single nucleotide polymorphism (SNP309) is found in the MDM2 promoter and is shown to increase the affinity of the transcriptional activator Sp1, resulting in higher levels of MDM2 RNA and protein and the subsequent attenuation of the p53 pathway. In humans, SNP309 is shown to associate with accelerated tumor formation in both hereditary and sporadic cancers. A model is proposed whereby SNP309 serves as a rate-limiting event in carcinogenesis.

在至少一半的癌症中，肿瘤抑制基因p53发生突变。因此，有理由认为p53应激反应通路中自然发生的多态性遗传变异可能决定个体对癌症的易感性。p53通路中的一个关键节点是MDM2蛋白，它是p53的直接负调控因子。在本报告中，在MDM2启动子中发现了一个单核苷酸多态性（SNP309），它被证明可增加转录激活因子Sp1的亲和力，从而导致MDM2 RNA和蛋白质水平升高以及随后p53通路的减弱。在人类中，SNP309被证明与遗传性和散发性癌症中肿瘤的加速形成有关。提出了一个模型，即SNP309在致癌过程中是一个限速事件。