Mechanism for acquiring the oncogenic function in mutated p53

在人类癌症中，P53基因的错义突变是最常见的基因突变(40%-75%)，通常位于高度保守的DNA结合蛋白质核心区。另一方面，p53基因的无义或移码突变(截短蛋白产生突变)的频率相对较低，约占所有p53突变的16%。因此，大多数p53突变的细胞都表达全长蛋白。大多数全长突变体P53被认为以显性负向方式抑制野生型P53的肿瘤抑制功能。然而，最近的研究表明，至少某些类型的全长错义突变体-P53可以通过获得新的致癌功能而积极地促进肿瘤的进展。在本研究中，我们发现了一个有趣的p53基因突变(TYS-P53：Asp281His)。TYS-P53不诱导细胞凋亡，但通过特定部位丝氨酸残基的磷酸化而明显诱导G1期停滞。因此，TYS-P53阻止了DNA损伤后细胞的凋亡，并可能加速了DNA损伤治疗导致的累积遗传改变和细胞恶性进展。我们还发现了P53基因的另一种致癌突变HNT-P53(Glu17Lys，His193Leu)。HNT-P53可能以一种转录无关的方式保护细胞免受DNA损伤所致的死亡，例如与线粒体蛋白或其他P53家族蛋白p63和p73的相互作用。P53基因的治疗前评估对于头颈部肿瘤患者的治疗非常重要，因为DNA损伤治疗的效果高度依赖于P53基因在肿瘤细胞中的状态。该检测系统可用于检测突变的p53基因的异常类型，突变的p53基因的详细信息可能为治疗策略提供有用的建议。

In human cancers, missense mutation in the p53 gene, often within the highly conserved DNA binding core domain of the protein, is the most frequent genetic alteration (40-75%). On the other hand, frequency of nonsense or frame shift mutations (truncated protein-producing mutation) in the p53 gene are relatively low, approximately 16% in all of the p53 mutation. Thus, most of the cells with p53 mutation express full-length proteins. Most of the full-length mutant-p53 is believed to inhibit the tumor suppressor function of wild type p53 in a dominant negative fashion. However, it is reported recently that at least certain types of full-length missense mutant-p53 can contribute actively to cancer progression through gain of new oncogenic function. In the present study, we found one interesting mutation of p53 gene (TYS-p53:Asp281His). TYS-p53 did not induce apoptosis, but clearly induced G1 arrest via phosphorylations of serine residue at the specific sites. Hence, TYS-p53 prevented cells from undergoing apoptosis after DNA damage, and might have accelerated the cumulative genetic alterations and malignant progression of the cells resulting from DNA-damaging therapy. We also found another oncogenic mutation of p53 gene, HNt-p53 (Glu17Lys, His193Leu). HNt-p53 might protect against cell death due to DNA damage in a transcription-independent manner, such as an interaction with the mitochondria proteins, or other p53 family proteins, p63 and p73. Pre-therapeutic evaluation of p53 gene is very important for treating patients with head and neck cancer, because the effect of DNA damaging therapy is highly dependent on the status of p53 gene in the tumor cells. This assay system can be utilized to identify the types of abnormality of mutated p53 gene, and the detail information of the mutated p53 gene might provide useful suggestions for the therapeutic strategy.