p53 loss-of-heterozygosity is a necessary prerequisite for mutant p53 stabilization and gain-of-function in vivo
p53 loss-of-heterozygosity is a necessary prerequisite for mutant p53 stabilization and gain-of-function in vivo
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DOI：
10.1038/cddis.2017.80
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发表时间：
2017-03-01
影响因子：
9
通讯作者：
Moll, Ute M.
中科院分区：
文献类型：
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作者：
Alexandrova, Evguenia M.;Mirza, Safia A.;Moll, Ute M.
TP53中的错义突变占癌症中所有P53改变的75%，导致高度稳定的突变型P53蛋白，这些蛋白不仅失去肿瘤抑制活性，而且经常获得致癌功能增益(GoF)。GOF在患者和小鼠身上表现为肿瘤发病速度加快，转移增加，耐药性增加，生存时间缩短。GOF的一个已知先决条件是突变的P53蛋白稳定，这本身与异常的蛋白质构象有关。然而，突变型p53稳定的其他决定因素可能存在。在这里，我们表明，在最初携带热点GOF等位基因R248Q(p53Q/+)的杂合子小鼠肿瘤中，突变的P53稳定和体内GOF的另一个必要条件是丢失剩余的野生型P53等位基因，称为杂合性丢失(LOH)。因此，在P53基因缺失频率较高的小鼠肿瘤(骨肉瘤和纤维肉瘤)中，我们发现突变的P53蛋白稳定(16/17例，94%)，与P53+/-肿瘤(GOF)相比，肿瘤的发生明显加快。相比之下，在低频率P53杂合性缺失的小鼠肿瘤(MMTV-Neu乳腺癌)中，突变型P53蛋白不稳定(16/20例，80%)，未观察到GOF。值得注意的是，人类基因组数据库(TCGA、METABRIC等)在所有检查的携带错义p53突变的肿瘤类型中，包括肉瘤和乳腺癌(有或没有HER2扩增)，都显示高度的P53杂合性缺失。这些数据虽然告诫并不是所有的遗传小鼠模型都能忠实地代表人类的情况，但首次证明了P53杂合性缺失是体内错义突变P53稳定和GOF的关键先决条件。
Missense mutations in TP53 comprise > 75% of all p53 alterations in cancer, resulting in highly stabilized mutant p53 proteins that not only lose their tumor-suppressor activity, but often acquire oncogenic gain-of-functions (GOFs). GOF manifests itself in accelerated tumor onset, increased metastasis, increased drug resistance and shortened survival in patients and mice. A known prerequisite for GOF is mutant p53 protein stabilization, which itself is linked to aberrant protein conformation. However, additional determinants for mutant p53 stabilization likely exist. Here we show that in initially heterozygous mouse tumors carrying the hotspot GOF allele R248Q (p53Q/+), another necessary prerequisite for mutant p53 stabilization and GOF in vivo is loss of the remaining wild-type p53 allele, termed loss-of-heterozygosity (LOH). Thus, in mouse tumors with high frequency of p53 LOH (osteosarcomas and fibrosarcomas), we find that mutant p53 protein is stabilized (16/17 cases, 94%) and tumor onset is significantly accelerated compared with p53+/- tumors (GOF). In contrast, in mouse tumors with low frequency of p53 LOH (MMTV-Neu breast carcinomas), mutant p53 protein is not stabilized (16/20 cases, 80%) and GOF is not observed. Of note, human genomic databases (TCGA, METABRIC etc.) show a high degree of p53 LOH in all examined tumor types that carry missense p53 mutations, including sarcomas and breast carcinomas (with and without HER2 amplification). These data - while cautioning that not all genetic mouse models faithfully represent the human situation - demonstrate for the first time that p53 LOH is a critical prerequisite for missense mutant p53 stabilization and GOF in vivo.