XAF1 IN P53 SIGNALING, APOPTOSIS AND TUMOR SUPPRESSION

P53 信号传导、细胞凋亡和肿瘤抑制中的 XAF1

基本信息

批准号：
10445617
负责人：
GERARD PAUL ZAMBETTI
金额：
$ 41.63万
依托单位：
ST. JUDE CHILDREN'S RESEARCH HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-03-03 至 2027-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10445617
关键词：
Address Adrenocortical carcinoma Age Alleles Apoptosis Apoptotic Azoxymethane Biochemical Brazil Carcinogens Cellular Stress Child Clinical Colon Carcinoma Databases Diagnosis Family Feedback General Population Genes Genetic Genetic Engineering Genomics Goals Haplotypes Heterogeneity High-Risk Cancer Human In Vitro Incidence Individual Inherited International Agency for Research on Cancer Knock-in Knock-in Mouse Knock-out Knockout Mice Malignant Neoplasms Mediating Modeling Mus Mutation Newborn Infant Nonsense Mutation Oncogenes Outcome Phenotype Physiological Population Predisposition Reporting Role Signal Transduction Sodium Dextran Sulfate Structure TP53 gene Tissues Transactivation Tumor Cell Line Tumor Suppression Tumor Suppressor Genes Tumor Suppressor Proteins XAF1 gene base cancer risk cell type colon carcinogenesis epigenetic silencing established cell line founder mutation gene function in vivo interest loss of function mouse model mutant mutant mouse model mutation carrier novel p53 Signaling Pathway sarcoma tumor tumorigenesis variant of unknown significance

项目摘要

ABSTRACT We previously identified the TP53-R337H founder mutation in a group of Brazilian children who developed adrenocortical carcinoma. A general population screen of 175,000 newborns demonstrated that 1 in 375 individuals from southern Brazil (Rio de Janeiro, Sao Paulo and Parana, total population 80-100 million) are carriers of this mutation. Surprisingly many of these carriers are at low risk of cancer and remain tumor free. Subsequent genomic analyses identified a nonsense mutation in the putative tumor suppressor XAF1 (E134*) in linkage with the TP53- R337H mutation in a subset of carriers. XAF1 is also reported to function in apoptosis within a positive feedback loop with p53, and its expression is frequently selected against by epigenetic silencing in a broad range of human tumors. Based on these findings we propose that XAF1- E134* cooperates with p53-R337H in promoting tumorigenesis. Consistent with this hypothesis we found that the double mutant haplotype is significantly enriched in carriers who developed cancer in general, sarcomas and multiple tumors. Building upon these observations we will study the physiological role of XAF1 in apoptosis and tumor suppression and whether the nonsense mutation cooperates with the TP53-R337H mutation in promoting tumorigenesis using knockin and knockout mouse models. We will address these questions in the following two Specific Aims: 1) Does XAF1 function as a physiologic proapoptotic tumor suppressor? and 2) Do XAF1- E134* and TP53-R337H cooperate to enhance tumor susceptibility? Together, these studies will establish how these mutations interact, and explain the high tumor incidence in individuals carrying both mutations. In doing so, we will more generally address the disparities in outcome among individuals carrying the same p53 mutation.

抽象的我们之前在一组巴西儿童中发现了 TP53-R337H 创始人突变，这些儿童发展为肾上腺皮质癌。对 175,000 名新生儿进行总体筛查表明，来自巴西南部（里约热内卢、圣保罗和圣保罗）的每 375 人中就有 1 人巴拉那州总人口80-1亿）是这种突变的携带者。令人惊讶的是其中有很多携带者患癌症的风险较低，并且保持无肿瘤状态。随后的基因组分析发现假定的肿瘤抑制因子 XAF1 (E134*) 中与 TP53- 相关的无义突变一部分携带者中存在 R337H 突变。据报道，XAF1 在细胞凋亡中发挥作用 p53 的正反馈环，其表达经常受到表观遗传的选择广泛的人类肿瘤沉默。基于这些发现，我们建议 XAF1- E134* 与 p53-R337H 协同促进肿瘤发生。与这个假设相符我们发现双突变单倍型在发展为一般癌症、肉瘤和多种肿瘤。基于这些观察，我们将研究 XAF1在细胞凋亡和肿瘤抑制中的生理作用是否是废话突变与TP53-R337H突变配合使用敲入促进肿瘤发生和基因敲除小鼠模型。我们将在以下两个具体目标中解决这些问题： 1) XAF1 是否具有生理性促凋亡肿瘤抑制因子的功能？ 2) 执行 XAF1- E134*与TP53-R337H协同增强肿瘤易感性？总之，这些研究将确定这些突变如何相互作用，并解释高肿瘤携带两种突变的个体的发病率。在此过程中，我们将更普遍地解决携带相同 p53 突变的个体之间的结果差异。