Characterization of a new cancer-associated mutant of p53 with a missense mutation (K351N) in the tetramerization domain
Characterization of a new cancer-associated mutant of p53 with a missense mutation (K351N) in the tetramerization domain
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DOI：
10.4161/cc.8.20.9910
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发表时间：
2009-10-15
期刊：
影响因子：
4.3
通讯作者：
Tuosto, Loretta
中科院分区：
文献类型：
--
作者：
Muscolini, Michela;Montagni, Elisa;Tuosto, Loretta
抑癌基因p53的失活是肿瘤发生和获得对药物诱导的细胞凋亡的抗性的关键。大多数改变是错义突变，发生在DNA结合结构域内。然而，很少有人知道在四聚化结构域（TD）的点突变。在这里，我们研究了一个新的p53突变体（赖氨酸351 Asn）的性质，在TD中确定的顺铂耐药卵巢癌细胞系（A2780 CIS）。我们发现K351N取代显著降低了p53四聚体的热力学稳定性，而不影响蛋白质的总体半衰期。此外，p53 K351 N结合DNA和反式激活其特异性靶基因启动子（如bax）的能力降低。p53亚细胞定位分析结果显示，K351N突变抑制了顺铂诱导的p53的核输出和胞浆积聚。这些结果将p53 K351 N鉴定为一种新的癌症相关突变体，其具有降低的肿瘤抑制活性和响应于凋亡刺激的改变的功能。
Inactivation of the tumor suppressor p53 is central to carcinogenesis and acquisition of resistance to drug-induced apoptosis. The majority of alterations are missense mutations and occur within the DNA-binding domain. However, little is known about the point mutations in the tetramerization domain (TD). Here we investigated the properties of a new p53 mutant (Lys 351 to Asn) in the TD identified in a cisplatin-resistant ovarian carcinoma cell line (A2780 CIS). We found that K351N substitution significantly reduces the thermodynamic stability of p53 tetramers without affecting the overall half-life of the protein. Moreover, p53 K351N has a reduced ability to bind DNA and to trans-activate its specific target gene promoters, such as bax. Data obtained from the analysis of p53 subcellular localization revealed that K351N mutation inhibits the nuclear export of p53 and accumulation in the cytoplasm induced by cisplatin treatment. These results identify p53 K351N as a new cancer associated mutant with reduced tumor suppressor activity and altered functions in response to apoptotic stimuli.