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Mechanism for acquiring the oncogenic function in mutated p53

突变p53获得致癌功能的机制

基本信息

批准号：
17592103
负责人：
KAWAMATA Hitoshi
金额：
$ 2.37万
依托单位：
Dokkyo Medical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17592103/
关键词：
oral cancer genetic diagnosis p53 oncogenic mutation p73 p53標的遺伝子ルシフェラーゼアッセイ

项目摘要

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.

在人类癌症中，p53基因中的错义突变（通常在蛋白质的高度保守的DNA结合核心结构域内）是最常见的遗传改变（40-75%）。另一方面，p53基因中无义突变或移码突变（截短的蛋白质产生突变）的频率相对较低，约占所有p53突变的16%。因此，大多数具有p53突变的细胞表达全长蛋白。大多数全长突变体p53被认为以显性负性方式抑制野生型p53的肿瘤抑制功能。然而，最近报道，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癌症进展。在本研究中，我们发现了一个有趣的p53基因突变（TYS-p53：Asp 281 His）。TYS-p53不诱导细胞凋亡，但通过丝氨酸残基在特定位点的磷酸化明显诱导G1期阻滞。因此，TYS-p53阻止了DNA损伤后的细胞凋亡，并可能加速了DNA损伤治疗引起的细胞的累积遗传改变和恶性进展。我们还发现了p53基因的另一个致癌突变HNt-p53（Glu 17 Lys，His 193 Leu）。HNt-p53可能以不依赖于转录的方式保护细胞免受DNA损伤引起的细胞死亡，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基因在头颈部肿瘤细胞中的表达状态决定了DNA损伤治疗的效果，因此，治疗前对p53基因的检测对于头颈部肿瘤的治疗具有重要意义。该检测系统可用于p53基因突变异常类型的鉴定，并可为临床治疗提供参考。