XAF1 IN P53 SIGNALING, APOPTOSIS AND TUMOR SUPPRESSION

摘要 我们先前在一组巴西儿童中发现了TP 53-R337 H创始者突变， 患上了肾上腺皮质癌对175，000名新生儿进行一般人群筛查 巴西南部（里约热内卢、圣保罗和 巴拉那，总人口80-100万）是这种突变的携带者。令人惊讶的是， 携带者患癌症的风险低，并且保持无肿瘤。随后的基因组分析确定了 在假定的肿瘤抑制因子XAF 1（E134*）中与TP 53- R337 H突变在一个子集的运营商。XAF 1也被报道在细胞凋亡中起作用， p53的正反馈环，其表达经常被表观遗传学选择性地抑制。 在广泛的人类肿瘤中沉默。基于这些发现，我们提出XAF 1- E134* 与p53-R337 H协同促进肿瘤发生。与该假设一致 我们发现，双突变单倍型在发展为 癌症，肉瘤和多发性肿瘤。基于这些观察，我们将研究 XAF 1在细胞凋亡和肿瘤抑制中的生理作用，以及XAF 1是否无意义 突变与TP 53-R337 H突变协同作用，通过敲入促进肿瘤发生 和敲除小鼠模型。我们将在以下两个具体目标中解决这些问题： 1)XAF 1是否作为生理性促凋亡肿瘤抑制因子发挥作用？和2）做XAF 1- E134* 和TP 53-R337 H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，并解释高肿瘤发生率。 携带这两种突变的个体的发病率。在这样做时，我们将更广泛地处理 携带相同p53突变的个体之间的结果差异。

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.