Nucleophosmin is required for DNA integrity and p19Arf protein stability
Nucleophosmin is required for DNA integrity and p19Arf protein stability
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DOI：
10.1128/mcb.25.20.8874-8886.2005
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发表时间：
2005-10-01
影响因子：
5.3
通讯作者：
Pelicci, PG
中科院分区：
文献类型：
--
作者：
Colombo, E;Bonetti, P;Pelicci, PG
核磷蛋白（NPM）是一种结合肿瘤抑制因子p53和p19（Arf）的核仁磷蛋白，被认为是核糖合成、细胞增殖和DNA损伤后生存所必需的。NPM基因是白血病和淋巴瘤中最常见的遗传改变靶点，但其在肿瘤发生中的作用尚不清楚。我们在这里报告的第一个表征的小鼠NPM基因敲除株。NPM表达的缺乏导致DNA损伤的积累、p53的激活、广泛的细胞凋亡和中期胚胎致死。从无效胚胎中分离的成纤维细胞不能生长并迅速获得衰老表型。将NPM突变转移到p53无效背景中挽救了体内细胞凋亡和体外成纤维细胞增殖。p53和NPM都无效的细胞比对照细胞生长得更快，并且更容易被激活的癌基因转化，例如突变的Ras或过表达的Myc。在没有NPM的情况下，Arf蛋白被排除在核仁之外，并且明显不稳定。我们的数据表明，NPM调节DNA的完整性，并通过Arf，抑制细胞增殖，并与一个假定的肿瘤抑制功能的NPM一致。
Nucleophosmin (NPM) is a nucleolar phosphoprotein that binds the tumor suppressors p53 and p19(Arf) and is thought to be indispensable for ribogenesis, cell proliferation, and survival after DNA damage. The NPM gene is the most frequent target of genetic alterations in leukemias and lymphomas, though its role in tumorigenesis is unknown. We report here the first characterization of a mouse NPM knockout strain. Lack of NPM expression results in accumulation of DNA damage, activation of p53, widespread apoptosis, and mid-stage embryonic lethality. Fibroblasts explanted from null embryos fail to grow and rapidly acquire a senescent phenotype. Transfer of the NPM mutation into a p53-null background rescued apoptosis in vivo and fibroblast proliferation in vitro. Cells null for both p53 and NPM grow faster than control cells and are more susceptible to transformation by activated oncogenes, such as mutated Ras or overexpressed Myc. In the absence of NPM, Arf protein is excluded from nucleoli and is markedly less stable. Our data demonstrate that NPM regulates DNA integrity and, through Arf, inhibits cell proliferation and are consistent with a putative tumor-suppressive function of NPM.