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 antiproliferative 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-of-gain and gain-of-function characteristics, distinguishing it from both wild type p53 and p53 loss. Implications: p53 frameshift mutants display a mixture of residual antiproliferative and neomorphic functions that may be differentially exploited for targeted therapy. This article is featured in Highlights of This Issue, [p. 1439][1] [1]: /lookup/volpage/19/1439?iss=9

中文翻译：

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p53 移码突变将功能丧失与独特的新形态活动结合起来

导致转录活性丧失的 p53 突变常见于多种癌症中。虽然其中大多数是位于中央 DNA 结合域内的错义突变，但由于各种核苷酸取代、插入或缺失，也可能发生截断和/或移码突变。这些变化导致含有过早终止密码子的 mRNAs 被翻译成一组不同的 C 末端截短蛋白。在这里，我们表征了从 U2OS 骨肉瘤和 HCT116 结直肠癌细胞系中的内源性 TP53 基因座表达的三种 p53 移码突变蛋白。这些突变体保留了完整的 DNA 结合结构域，但显示出改变的寡聚化特性。尽管它们的表达水平异常高，它们大多不具有转录活性，并且不能启动野生型 p53 特有的刺激诱导的转录程序。然而，其中一种变体 p53 蛋白 I332fs*14 类似于天然表达的 TAp53 同种型 β 和 γ，保留了一些残留的抗增殖活性，并且可以在 HCT116 细胞中诱导细胞衰老。表达该突变体的细胞在迁移测定中也表现出运动性降低。因此，这种 p53 变体表现出增益损失和功能增益特征的组合，将其与野生型 p53 和 p53 损失区分开来。启示：p53 移码突变体显示出残余的抗增殖和新形态功能的混合物，可用于靶向治疗。这篇文章被收录在本期的亮点中，[p. 1439] [1] [1]：