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：
10583516
负责人：
GERARD PAUL ZAMBETTI
金额：
$ 40.8万
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/10583516
关键词：
Address Adrenocortical carcinoma Age Alleles Apoptosis Apoptotic Azoxymethane Biochemical Brazil Carcinogens Cellular Stress Child Clinical Colon Carcinoma Databases Diagnosis Disparity 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 cancer risk cell type colon carcinogenesis epigenetic silencing established cell line founder mutation gain of function gene function in vivo interest loss of function mouse model mutant mutant mouse model mutation carrier novel p53 Signaling Pathway sarcoma segregation 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.

抽象的我们以前在一组巴西儿童中确定了TP53-R337H的创始人突变发展了肾上腺皮质癌。 175,000名新生儿的一般人口屏幕证明来自巴西南部的375个人中有1人（里约热内卢，圣保罗和 Parana，总人口80-1亿）是该突变的载体。令人惊讶的是其中许多携带者的癌症风险很低，并且仍然没有肿瘤。随后确定的基因组分析与TP53-链接的假定肿瘤抑制XAF1（E134*）中的无意义突变载体子集中的R337H突变。 XAF1还据报道在A内作用带有p53的正反馈循环，其表达经常被表观遗传选择沉默在广泛的人类肿瘤中。根据这些发现，我们建议xaf1- E134*与p53-R337H合作促进肿瘤发生。与这个假设一致我们发现，双突变单倍型在开发的载体中显着丰富总体上，肉瘤和多个肿瘤。基于这些观察，我们将研究 XAF1在凋亡和肿瘤抑制中的生理作用以及是否胡说八道突变与TP53-R337H突变合作，使用敲击蛋白促进肿瘤发生和淘汰鼠标模型。我们将在以下两个具体目标中解决这些问题： 1）XAF1是否充当生理促凋亡肿瘤抑制剂？ 2）做xaf1- E134*和TP53-R337H配合以增强肿瘤敏感性？这些研究将共同确定这些突变的相互作用，并解释高肿瘤携带这两个突变的个体的发病率。这样，我们将更普遍地解决携带相同p53突变的个体的结果差异。