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首页> 外文期刊>Biological chemistry >Mutant p53: gain-of-function oncoproteins and wild-type p53 inactivators.
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Mutant p53: gain-of-function oncoproteins and wild-type p53 inactivators.

机译：突变体p53：发挥作用癌蛋白和野生型p53灭失剂。

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摘要

Cancers frequently express mutant forms of the p53 transcription factor and tumor suppressor. Early observations indicated that mutant p53 can enhance the malignancy of tumor cells and immortalize primary cells. Immortalization is also frequently observed in primary cell cultures upon loss of wild-type (wt) p53, and since p53 acts as a tetramer and mutant p53 can hetero-oligomerize with the wild type, a significant number of effects are assigned to mutant p53 acting as a dominant-negative protein. Dominance depends on the ratio of the proteins as well as on the position of the mutated amino acid residue. Mutations that alter the tertiary structure can give rise to proteins capable of forcing upon wt p53 a non-wild-type conformation, and hetero-tetrameric complexes with altered conformation are impaired for DNA binding. Mutations that affect DNA contact sites compromise DNA binding in dependence on the affinity of the hetero-tetrameric complex for a p53 recognition motif. In addition to dominance, mutant p53 can exert oncogenic functions independently of the inactivation of wt p53. Such gain-of-function manifests itself in the enhancement of tumorigenicity, of metastatic potential, and of survival and therapy resistance of wt p53-null tumor cells. The significance of dominant-negative function and gain-of-function for the various cancer phenotypes, for prognosis and for the success of therapy are currently unclear and subject of study.
机译：癌症经常表达p53转录因子和肿瘤抑制剂的突变形式。早期观察结果表明突变体P53可以增强肿瘤细胞恶性肿瘤并使原代细胞永生化。在野生型（WT）P53损失时，在原发性细胞培养物中也经常观察到永生化，因为P53用作四聚体和突变体P53可以用野生型杂种异源化，因此将大量的效果分配给突变体P53作用作为主要阴性蛋白质。优势取决于蛋白质的比例以及突变氨基酸残基的位置。改变三级结构的突变可以产生能够迫使WT p53迫使非野生型构象的蛋白质，并且对于DNA结合损害具有改变的构象的杂四聚体络合物。影响DNA接触位点的突变依赖于杂四聚体复合物对P53识别基序的亲和力来抑制DNA结合。除了优势之外，突变体P53还可以独立于WT P53的失活施用致癌功能。这种功能性表现出在肿瘤内的增强，转移潜力和WT p53-零肿瘤细胞的存活和治疗抗性的增强。目前不清楚，用于预后和治疗成功的主要负函数和函数增益的重要性目前不清楚并进行研究。

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