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缺乏原癌基因CAN/Nup214的小鼠胚胎中出现G2期阻滞及核质转运受损。

G2 arrest and impaired nucleocytoplasmic transport in mouse embryos lacking the proto-oncogene CAN/Nup214.

作者信息

van Deursen J, Boer J, Kasper L, Grosveld G

机构信息

Department of Genetics, St Jude Children's Research Hospital, Memphis, TN 38105, USA.

出版信息

EMBO J. 1996 Oct 15;15(20):5574-83.

PMID:8896451
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC452302/
Abstract

The vertebrate nucleopore complex (NPC) is a 125 MDa multiprotein assembly that mediates nucleocytoplasmic transport. One of its components, CAN/Nup214, is an FXFG repeat-containing protein known to be involved in myeloid leukemia in humans. We have devised a powerful genetic approach, using maternally derived protein in murine null embryos, to show that CAN/ Nup214 is essential for NPC function in vivo. We demonstrate that CAN-/- mouse embryonic stem (ES) cells are not viable and that CAN-/- embryos die in utero between 4.0 and 4.5 days postcoitum, following the depletion of their CAN from maternal sources. In 3.5-day-old mutant embryos, cultured in vitro, progressive depletion of CAN leads to cell cycle arrest in G2 phase, and eventually to blastocoel collapse, impaired NLS-mediated protein uptake and nuclear accumulation of polyadenylated RNA. Remarkably, these defective CAN-depleted embryos do not display any gross morphological abnormalities in their nuclear envelopes or NPCs. Our data suggest that CAN is critical to cell cycle progression and required for both nuclear protein import and mRNA export.

摘要

脊椎动物核孔复合体（NPC）是一种125兆道尔顿的多蛋白组装体，介导核质运输。其组成成分之一CAN/Nup214是一种含有FXFG重复序列的蛋白，已知与人类髓系白血病有关。我们设计了一种强大的遗传学方法，利用小鼠无效胚胎中母源蛋白，来证明CAN/Nup214在体内对NPC功能至关重要。我们证明，CAN基因敲除的小鼠胚胎干细胞无法存活，且CAN基因敲除的胚胎在合子期后4.0至4.5天死于子宫内，此时其母源的CAN已耗尽。在体外培养的3.5天大的突变胚胎中，CAN的逐渐耗尽导致细胞周期在G2期停滞，最终导致囊胚腔塌陷、核定位信号介导的蛋白质摄取受损以及多聚腺苷酸化RNA的核内积累。值得注意的是，这些CAN耗尽的缺陷胚胎在其核膜或NPC中未表现出任何明显的形态异常。我们的数据表明，CAN对细胞周期进程至关重要，并且是核蛋白输入和mRNA输出所必需的。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8fcc/452302/01f65c34627b/emboj00020-0104-a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8fcc/452302/44556afb0c3d/emboj00020-0099-a.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8fcc/452302/44556afb0c3d/emboj00020-0099-a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8fcc/452302/97655bea9491/emboj00020-0100-a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8fcc/452302/ef1e533235b8/emboj00020-0101-a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8fcc/452302/0159fad7f480/emboj00020-0103-a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8fcc/452302/01f65c34627b/emboj00020-0104-a.jpg

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本文引用的文献

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Pores for thought: nuclear pore complex proteins.思考的孔隙：核孔复合体蛋白
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Nucleocytoplasmic transport.核质运输
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Importins/karyopherins meet nucleoporins.输入蛋白/核转运蛋白与核孔蛋白相遇。
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Traumatic injury compromises nucleocytoplasmic transport and leads to TDP-43 pathology.创伤性损伤会损害核质转运，并导致 TDP-43 病理学。
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The nuclear pore proteins Nup88/214 and T-cell acute lymphatic leukemia-associated NUP214 fusion proteins regulate Notch signaling.核孔蛋白 Nup88/214 和 T 细胞急性淋巴细胞白血病相关的 NUP214 融合蛋白调节 Notch 信号通路。
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