Cytoplasmic nucleophosmin has elevated T199 phosphorylation upon which G2/M phase progression is dependent.
Cytoplasmic nucleophosmin has elevated T199 phosphorylation upon which G2/M phase progression is dependent.
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DOI：
10.1038/srep11777
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发表时间：
2015-06-30
影响因子：
4.6
通讯作者：
Lim TM
中科院分区：
文献类型：
--
作者：
Chan N;Lim TM
核磷蛋白（NPMc）的细胞质突变大约在三分之一的急性髓性白血病（AML）病例中发现，并且与正常核型高度相关。鉴于之前的研究主要集中在wtNPM在中心体复制中的作用，我们进一步阐明了NPM在细胞周期中的作用，利用增加的NPMc细胞质负荷。NPMc的过表达导致T199上NPM的磷酸化增加，S4的磷酸化程度较低。T199磷酸化依赖于cdk2，但cdk2激活因子未升高。在抑制cdk2后，npmc过表达的细胞比wtNPM或GFP对偶物表现出更大的G2/M期阻滞。但2中心体细胞的数量并没有相应增加。这表明这种阻滞是由中心体复制的延迟引起的，很可能是由于未磷酸化的NPMc引起的中心体复制的抑制。总之，这些结果表明T199的磷酸化在表达npmc的细胞的有丝分裂过程中是重要的。这进一步支持了NPMc与AML正常核型相关的假设，因为较高的细胞质NPM负荷可以更好地抑制中心体过度复制，否则中心体过度复制会导致有丝分裂期间染色体的不平等分离，从而导致非整倍体和其他基因组不稳定性。
The cytoplasmic mutant of nucleophosmin (NPMc) is found approximately in one-third of acute myeloid leukemia (AML) cases and is highly associated with normal karyotype. Whereas previous studies have focused on wtNPM in centrosome duplication, we further elucidate the role of NPM in the cell cycle by utilizing the increased cytoplasmic load of NPMc. Overexpression of NPMc causes increased phosphorylation of NPM on T199 and, to a lesser degree, S4. T199 phosphorylation is dependent on cdk2 but activators of cdk2 were not elevated. Upon inhibition of cdk2, NPMc-overexpressing cells demonstrate a greater G2/M phase arrest than wtNPM or GFP counterparts. However, the number of cells with 2 centrosomes did not increase concordantly. This suggests that the arrest was caused by a delay in centrosome duplication, most likely due to the inhibition of centrosome duplication caused by unphosphorylated NPMc. Overall, these results suggest that the phosphorylation of T199 is important in the mitotic progression of NPMc-expressing cells. This further supports the hypothesis that NPMc is associated with normal karyotypes in AML because the higher cytoplasmic load of NPM can better suppress centrosome overduplication which would otherwise result in unequal segregation of chromosomes during mitosis, leading to aneuploidy and other genomic instabilities.
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DOI：
10.1038/nrm3494
发表时间：
2013-01
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
--
影响因子：
158.5
作者：
Falini, B;Mecucci, C;Martelli, MF
通讯作者：
Martelli, MF
影响因子：
21.3
作者：
Colombo, E;Marine, JC;Pelicci, PG
通讯作者：
Pelicci, PG
影响因子：
20.3
作者：
Falini, Brunangelo;Bolli, Niccolò;Nicoletti, Ildo
通讯作者：
Nicoletti, Ildo
影响因子：
4.3
作者：
Tarapore, Pheruza;Okuda, Masaru;Fukasawa, Kenji
通讯作者：
Fukasawa, Kenji