p53 Frameshift Mutations Couple Loss-of-Function with Unique Neomorphic Activities.
p53 Frameshift Mutations Couple Loss-of-Function with Unique Neomorphic Activities.
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DOI：
10.1158/1541-7786.mcr-20-0691
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发表时间：
2021-09
期刊：
影响因子：
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通讯作者：
Prives C
中科院分区：
文献类型：
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作者：
Tong DR;Zhou W;Katz C;Regunath K;Venkatesh D;Ihuegbu C;Manfredi JJ;Laptenko O;Prives C
导致转录活性丧失的p53突变通常在多种类型的癌症中发现。虽然其中大多数是错义突变，映射在中心DNA结合域，但也可以由于各种核苷酸替换、插入或缺失而发生截断和/或移码突变。这些变化导致含有过早终止密码子的mRNA被翻译成一组不同的C末端截短蛋白质。在这里，我们研究了U2OS骨肉瘤和HCT116结直肠癌细胞系中内源性TP53基因表达的三种P53移码突变蛋白。这些突变体保留了完整的DNA结合域，但显示了改变的寡聚特性。尽管它们的表达水平异常高，但它们大多在转录上不活跃，无法启动野生型p53特有的刺激诱导的转录程序。然而，其中一种与自然表达的TAp53亚型β和γ相似的突变型P53蛋白I332fs*14在HCT116细胞中保留了一定的抗增殖活性，并能诱导细胞衰老。表达该突变体的细胞在迁移试验中也表现出运动性降低。因此，这种P53变异体表现出功能丧失和功能获得特征的组合，区别于野生型P53和P53丢失。
p53 mutations that result in loss of transcriptional activity are commonly found in numerous types of cancer. While the majority of these are missense mutations that map within the central DNA binding domain, truncations and/or frameshift mutations can also occur due to various nucleotide substitutions, insertions, or deletions. These changes result in mRNAs containing premature stop codons that are translated into a diverse group of C-terminally truncated proteins. Here we characterized three p53 frameshift mutant proteins expressed from the endogenous TP53 locus in U2OS osteosarcoma and HCT116 colorectal cancer cell lines. These mutants retain intact DNA binding domains but display altered oligomerization properties. Despite their abnormally high expression levels, they are mostly transcriptionally inactive and unable to initiate a stimuli-induced transcriptional program characteristic of wild type p53. However, one of these variant p53 proteins, I332fs*14, which resembles naturally expressed TAp53 isoforms β and γ, retains some residual anti-proliferative activity and can induce cellular senescence in HCT116 cells. Cells expressing this mutant also display decreased motility in migration assays. Hence, this p53 variant exhibits a combination of loss- and gain-of-function characteristics, distinguishing it from both wild type p53 and p53 loss.