p53 Variants in Cancer Risk and Therapy

 描述（申请人提供）：p53抑癌基因是人类癌症中最重要的基因之一。与绝大多数癌基因和抑癌基因不同，TP53 基因的特点是编码区存在改变 p53 功能的单核苷酸多态性。几年前，我们报道了 TP53 氨基酸 47（Pro47Ser，rs1800371）的多态性发生在 1:40 的非洲裔美国人和高达 1:10 的非洲人中；这种多态性显着损害了 p53 在关键残基丝氨酸 46 上的磷酸化，并且还显着损害了 p5 的凋亡能力。为了评估这种多态性对癌症风险和治疗的影响，我们创建了 S47 变体的小鼠模型，与野生型 p53 进行比较。我们还分析了与 WT p53 相比 S47 变体纯合的人淋巴母细胞系。我们在小鼠和人类细胞中都发现，S47 变体在应激反应中诱导细胞凋亡的能力显着降低，同时反式激活 p53 靶基因子集（Noxa、GLS2 和 Sco2）的能力也降低，同时丝氨酸 46 无法磷酸化。我们发现，带有 S47 的细胞对许多化疗药物具有显着的耐药性，但对其他化疗药物的敏感性增加。令人惊讶的是，我们发现S47小鼠容易患癌症，而且S47雄性小鼠会出现自发性前列腺增生。在初步人体研究中，我们显示的数据表明 S47 等位基因可能是非裔美国男性患前列腺癌的重要危险因素。该提案的广泛、长期目标是检验以下假设：S47 功能受损会导致抑制前列腺癌发生和进展的能力降低。我们还试图检验 S47 个体的化疗可以个性化的假设。有两个目标。在目标 1 中，我们的 WT 和 S47 小鼠模型将用于测试 S47 在前列腺癌的发生、进展和化疗中的功能。在目标 2 中，我们将分析来自非裔美国男性的人类前列腺癌样本，并检验 S47 变异与前列腺癌风险和/或侵袭性增加相关的假设。重要的是，每个目标的信息将用于告知另一个目标。为了实现这些目标，我们结合了四个实验室的专业知识，其中三个实验室位于同一校区（Murphy、Altieri 和 Rebbeck），其中两个实验室（Rebbeck 和 Isaacs）在人类前列腺癌流行病学方面拥有长期的专业知识。每个小组在小鼠癌症模型、p53 功能和非洲裔男性前列腺癌流行病学方面都有独特且互补的专业知识。这项拟议的研究标志着首次评估这种有害多态性对非洲人后裔癌症风险和治疗的影响。

 DESCRIPTION (provided by applicant): The p53 tumor suppressor gene is one of the most important genes in human cancer. Unlike the overwhelming majority of oncogenes and tumor suppressor genes, the TP53 gene is distinguished by the existence of single nucleotide polymorphisms in the coding region that alter p53 function. Several years ago we reported that a polymorphism at amino acid 47 (Pro47Ser, rs1800371) of TP53 occurs in 1:40 African Americans and up to 1:10 of Africans; this polymorphism markedly impairs the phosphorylation of p53 on a critical residue, serine 46, and also significantly impairs the apoptotic ability of p5. In order to assess the impact of this polymorphism on cancer risk and therapy, we created a mouse model for the S47 variant, compared to wild type p53. We also analyzed human lymphoblastoid cell lines that are homozygous for the S47 variant, compared to WT p53. We show in both our mice and in human cells that the S47 variant has markedly decreased ability to induce apoptosis in response to stress, along with decreased ability to transactivate a subset of p53 target genes (Noxa, GLS2 and Sco2), accompanied by a failure to be phosphorylated on serine 46. We show that cells with S47 have dramatic resistance to many chemotherapeutic agents, yet increased sensitivity to others. Surprisingly, we find that S47 mice are cancer- prone, and further that S47 male mice develop spontaneous prostate hyperplasia. In preliminary human studies we show data indicating that the S47 allele may be a significant risk factor for prostate cancer in African American men. The broad, long term objective of this proposal is to test the hypothesis that the impaired function of S47 leads to reduced ability to suppress prostate cancer initiation and progression. We also seek to test the hypothesis that chemotherapy in S47 individuals can be personalized. There are two aims. In Aim 1, our mouse models for WT and S47 will be used to test the function of S47 in the initiation, progression, and chemotherapy of prostate cancer. In Aim 2, we will analyze human prostate cancer samples from African American men, and test the hypothesis that the S47 variant is associated with increased prostate cancer risk and/or aggressiveness. Importantly, information from each aim will be used to inform the other. For these goals, we have combined the expertise of four laboratories, three of which are located on the same campus (Murphy, Altieri and Rebbeck), and two of which have long-standing expertise in the epidemiology of human prostate cancer (Rebbeck and Isaacs). Each group has unique and complementary expertise in mouse models of cancer, p53 function, and epidemiology of prostate cancer in men of African descent. The proposed research marks the first time that the impact of this deleterious polymorphism on cancer risk and therapy in individuals of African descent will be assessed.