The cell proliferation antigen Ki-67 organises heterochromatin.
The cell proliferation antigen Ki-67 organises heterochromatin.
复制标题
DOI：
10.7554/elife.13722
复制
发表时间：
2016-03-07
期刊：
影响因子：
7.7
通讯作者：
Fisher D
中科院分区：
文献类型：
--
作者：
Sobecki M;Mrouj K;Camasses A;Parisis N;Nicolas E;Llères D;Gerbe F;Prieto S;Krasinska L;David A;Eguren M;Birling MC;Urbach S;Hem S;Déjardin J;Malumbres M;Jay P;Dulic V;Lafontaine DLj;Feil R;Fisher D
抗原Ki-67是一种在哺乳动物增殖细胞中表达的核蛋白。它被广泛应用于癌症组织病理学，但其功能尚不清楚。在这里，我们表明Ki-67控制异染色质组织。改变Ki-67表达水平对细胞增殖无显著影响。Ki-67突变小鼠发育正常，缺乏Ki-67的细胞增殖效率高。相反，分化组织中Ki-67表达的上调并不能阻止细胞周期阻滞。Ki-67相互作用物包括参与核仁过程和染色质调节因子的蛋白。Ki-67缺失破坏核发生，但不抑制pre-rRNA加工。相反，它改变了基因表达。Ki-67沉默对染色质组织也有广泛的影响，破坏异染色质压实和远程基因组相互作用。组蛋白H3K9和H4K20的三甲基化在细胞核内被重新定位。最后，过表达人或爪蟾Ki-67诱导异位异染色质形成。总之，我们的研究结果表明，增殖细胞中的Ki-67表达在空间上组织异染色质，从而控制基因表达。DOI: http://dx.doi.org/10.7554/eLife.13722.001活细胞分裂成两部分产生新的细胞。在哺乳动物中，细胞分裂受到严格控制，因此在任何时候，体内只有特定的细胞群在活跃地分裂。然而，一些细胞可能会逃脱这些控制，从而迅速分裂并形成肿瘤。一种叫做Ki-67的蛋白质只在活跃分裂的细胞中产生，它位于细胞核中，细胞核是包含细胞大部分DNA的结构。研究人员经常使用Ki-67作为标志物来识别癌症患者组织样本中哪些细胞正在活跃分裂，先前的研究表明，细胞分裂需要Ki-67。然而，这种蛋白质的确切作用尚不清楚。在细胞分裂之前，它们需要使用称为核糖体的分子机器制造大量的新蛋白质，有人认为Ki-67有助于产生核糖体。现在，Sobecki等人利用基因技术研究了Ki-67在小鼠中的作用。实验表明，细胞在实验室中分裂或制造核糖体并不需要Ki-67。相反，Ki-67改变了DNA在细胞核中的包装方式。小鼠细胞中Ki-67的缺失导致DNA变得不那么紧密，进而改变了这些细胞中基因的活性。Sobecki等人还发现了许多与Ki-67相互作用的其他蛋白质，因此本研究的下一步是了解Ki-67如何在分子水平上改变DNA包装。另一个未来的挑战将是发现抑制Ki-67的活性是否可以阻碍癌细胞的生长。DOI: http://dx.doi.org/10.7554/eLife.13722.002
Antigen Ki-67 is a nuclear protein expressed in proliferating mammalian cells. It is widely used in cancer histopathology but its functions remain unclear. Here, we show that Ki-67 controls heterochromatin organisation. Altering Ki-67 expression levels did not significantly affect cell proliferation in vivo. Ki-67 mutant mice developed normally and cells lacking Ki-67 proliferated efficiently. Conversely, upregulation of Ki-67 expression in differentiated tissues did not prevent cell cycle arrest. Ki-67 interactors included proteins involved in nucleolar processes and chromatin regulators. Ki-67 depletion disrupted nucleologenesis but did not inhibit pre-rRNA processing. In contrast, it altered gene expression. Ki-67 silencing also had wide-ranging effects on chromatin organisation, disrupting heterochromatin compaction and long-range genomic interactions. Trimethylation of histone H3K9 and H4K20 was relocalised within the nucleus. Finally, overexpression of human or Xenopus Ki-67 induced ectopic heterochromatin formation. Altogether, our results suggest that Ki-67 expression in proliferating cells spatially organises heterochromatin, thereby controlling gene expression. DOI: http://dx.doi.org/10.7554/eLife.13722.001 Living cells divide in two to produce new cells. In mammals, cell division is strictly controlled so that only certain groups of cells in the body are actively dividing at any time. However, some cells may escape these controls so that they divide rapidly and form tumors. A protein called Ki-67 is only produced in actively dividing cells, where it is located in the nucleus – the structure that contains most of the cell’s DNA. Researchers often use Ki-67 as a marker to identify which cells are actively dividing in tissue samples from cancer patients, and previous studies indicated that Ki-67 is needed for cells to divide. However, the exact role of this protein was not clear. Before cells can divide they need to make large amounts of new proteins using molecular machines called ribosomes and it has been suggested that Ki-67 helps to produce ribosomes. Now, Sobecki et al. used genetic techniques to study the role of Ki-67 in mice. The experiments show that Ki-67 is not required for cells to divide in the laboratory or to make ribosomes. Instead, Ki-67 alters the way that DNA is packaged in the nucleus. Loss of Ki-67 from mice cells resulted in DNA becoming less compact, which in turn altered the activity of genes in those cells. Sobecki et al. also identified many other proteins that interact with Ki-67, so the next step following on from this research is to understand how Ki-67 alters DNA packaging at the molecular level. Another future challenge will be to find out if inhibiting the activity of Ki-67 can hinder the growth of cancer cells. DOI: http://dx.doi.org/10.7554/eLife.13722.002