Tsai Robert Y L, McKay Ronald D G
Laboratory of Molecular Biology, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA.
Genes Dev. 2002 Dec 1;16(23):2991-3003. doi: 10.1101/gad.55671.
The unique property of stem cells to self-renew suggests specific mechanisms that regulate their cell-cycle progression. In the present study, we identify a novel protein, nucleostemin, found in the nucleoli of CNS stem cells, embryonic stem cells, and several cancer cell lines and preferentially expressed by other stem cell-enriched populations. It contains an N-terminal basic domain and two GTP-binding motifs. When stem cells differentiate, nucleostemin expression decreases rapidly prior to cell-cycle exit both in vitro and in vivo. Depletion or overexpression of nucleostemin reduces cell proliferation in CNS stem cells and transformed cells. Mutation analysis indicates that excessive nucleostemin, particularly mutants that lack the GTP-regulatory domain, prevents cells from entering mitosis and causes apoptosis in a p53-dependent manner. The N-terminal basic domain specifies nucleolar localization, the p53 interaction, and is required for the cell death caused by overexpression. This work describes a novel nucleolar mechanism that controls the cell-cycle progression in CNS stem cells and cancer cells.
干细胞自我更新的独特特性提示了调控其细胞周期进程的特定机制。在本研究中，我们鉴定出一种新蛋白——核仁素，它存在于中枢神经系统干细胞、胚胎干细胞以及几种癌细胞系的核仁中，并在其他富含干细胞的群体中优先表达。它包含一个N端碱性结构域和两个GTP结合基序。当干细胞分化时，核仁素的表达在体外和体内细胞周期退出之前均迅速降低。核仁素的缺失或过表达会降低中枢神经系统干细胞和转化细胞的增殖。突变分析表明，过量的核仁素，特别是缺乏GTP调节结构域的突变体，会阻止细胞进入有丝分裂并以p53依赖的方式导致细胞凋亡。N端碱性结构域决定核仁定位、p53相互作用，并且是过表达引起细胞死亡所必需的。这项工作描述了一种控制中枢神经系统干细胞和癌细胞细胞周期进程的新的核仁机制。
