Nucleophosmin regulates the stability and transcriptional activity of p53
Nucleophosmin regulates the stability and transcriptional activity of p53
复制标题
DOI：
10.1038/ncb814
复制
发表时间：
2002-07-01
影响因子：
21.3
通讯作者：
Pelicci, PG
中科院分区：
文献类型：
--
作者：
Colombo, E;Marine, JC;Pelicci, PG
核磷蛋白(NPM)是一种普遍表达的核仁磷酸蛋白，持续穿梭于细胞核和细胞质之间(1)。它被认为在核糖体蛋白的组装和运输中发挥作用(2)，也作为一种分子伴侣防止蛋白质在拥挤的核仁环境中聚集(3)。NPM基因参与了几种肿瘤相关的染色体易位，导致了保留NPM氨基末端的融合蛋白的形成，包括NPM-ALK(4)，NPM-RAR(5)和NPM-MLF1(参考文献)。6)。通常认为，NPM组分并不参与这些融合蛋白(7)的转化潜力，而是为各种NPM伙伴(ALK、RAR、MLF1)的寡聚和致癌转化提供了一个二聚化界面。在这里，我们发现NPM直接与肿瘤抑制基因P53相互作用，调节P53在不同类型的应激后稳定性和转录激活的增加，并通过在二倍体成纤维细胞中的过度表达来诱导P53依赖的早衰。这些发现表明NPM是P53的重要调节因子，并提示NPM融合蛋白对NPM功能的改变可能导致肿瘤中P53的失控。
Nucleophosmin (NPM) is a ubiquitously expressed nucleolar phosphoprotein that continuously shuttles between the nucleus and cytoplasm(1). It has been proposed to function in ribosomal protein assembly and transport(2), and also as a molecular chaperone that prevents proteins from aggregating in the crowded environment of the nucleolus(3). The NPM gene is involved in several tumour-associated chromosome translocations, which have resulted in the formation of fusion proteins that retain the amino terminus of NPM, including NPM-ALK(4), NPM-RAR(5) and NPM-MLF1 (ref. 6). It is generally thought that the NPM component is not involved in the transforming potential of these fusion proteins(7), but instead provides a dimerization interface for the oligomerization and the oncogenic conversion of the various NPM partners (ALK, RAR, MLF1). Here we show that NPM interacts directly with the tumour suppressor p53, regulates the increase in stability and transcriptional activation of p53 after different types of stress, and induces p53-dependent premature senescence on overexpression in diploid fibroblasts. These findings indicate that NPM is a crucial regulator of p53 and suggest that alterations of the NPM function by NPM fusion proteins might lead to deregulation of p53 in tumours.