XAF1 IN P53 SIGNALING, APOPTOSIS AND TUMOR SUPPRESSION

摘要 我们之前在一组巴西儿童中发现了TP53-R337H创始人突变 患上了肾上腺皮质癌。17.5万名新生儿的一般人口筛查 显示来自巴西南部(里约热内卢、圣保罗和)的375人中有1人 巴拉那州，总人口8000万-1亿)是这种突变的携带者。令人惊讶的是，其中许多 携带者患癌症的风险很低，而且没有肿瘤。随后的基因组分析确定了 肿瘤抑制基因XAF1(E134*)与TP53连锁的无义突变 部分携带者的R337H突变。据报道，XAF1还在细胞凋亡中发挥作用 与P53的正反馈循环，其表达经常被表观遗传学选择 在广泛的人类肿瘤中沉默。基于这些发现，我们提出了XAF1- E134*与P53-R337H协同促进肿瘤发生。与这一假设一致 我们发现，双突变单倍型在罹患 癌症、肉瘤和多发性肿瘤。在这些观察的基础上，我们将研究 XAF1在细胞凋亡和肿瘤抑制中的生理作用以及是否无稽之谈 突变与TP53-R337H突变通过敲击协同促进肿瘤发生 和基因敲除的小鼠模型。我们将从以下两个具体目标来解决这些问题： 1)XAF1是否作为生理性促凋亡肿瘤抑制因子发挥作用？和2)做XAF1- E134*和TP53-R337H协同增强肿瘤易感性？ 总之，这些研究将确定这些突变是如何相互作用的，并解释高肿瘤 携带这两种突变的个体的发病率。在这样做的过程中，我们将更广泛地解决 携带相同p53突变的个体之间的结局差异。

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.