Nuclear pore protein NUP88 activates anaphase - promoting complex to promote aneuploidy
Nuclear pore protein NUP88 activates anaphase - promoting complex to promote aneuploidy
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DOI：
10.1172/jci82277
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发表时间：
2016-02-01
影响因子：
15.9
通讯作者：
van Deursen, Jan M.
中科院分区：
文献类型：
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作者：
Naylor, Ryan M.;Jeganathan, Karthik B.;van Deursen, Jan M.
核孔复合蛋白 NUP88 在侵袭性人类癌症中经常升高，并与患者生存率降低相关；然而，目前尚不清楚 NUP88 过度表达是否以及如何驱动肿瘤发生。在这里，我们证明过度表达 NUP88 的小鼠容易患癌症并形成肠道肿瘤。为了确定 NUP88 的过度表达是否会驱动肿瘤发生，我们设计了具有强力霉素诱导表达 Nup88 的转基因小鼠。令人惊讶的是，NUP88 过度表达并没有改变全局核运输，而是非整倍性和染色体不稳定的有效诱导物。我们确定 NUP88 以及核转运因子 NUP98 和 RAE1 组成一个调节网络，抑制后期促进复合物/环体 (APC/C) 的有丝分裂前活性。当过度表达时，NUP88 将 NUP98-RAE1 与 APC/C-CDH1 隔离，触发 Polo 样激酶 1 (PLK1)（一种肿瘤抑制因子和多任务有丝分裂激酶）的蛋白水解。 PLK1 的有丝分裂前破坏会破坏中心体分离，导致有丝分裂纺锤体不对称、裂线微管-着丝粒附着、滞后染色体和非整倍性。这些效应通过 PLK1 不足得到复制，表明 PLK1 是与 NUP88 过表达相关的有丝分裂缺陷的原因。这些发现表明，NUP88-NUP98-RAE1-APC/C-CDH1 轴有助于非整倍性，并表明它可能在多种人类癌症的起始阶段失调。
The nuclear pore complex protein NUP88 is frequently elevated in aggressive human cancers and correlates with reduced patient survival; however, it is unclear whether and how NUP88 overexpression drives tumorigenesis. Here, we show that mice overexpressing NUP88 are cancer prone and form intestinal tumors. To determine whether overexpression of NUP88 drives tumorigenesis, we engineered transgenic mice with doxycycline-inducible expression of Nup88. Surprisingly, NUP88 overexpression did not alter global nuclear transport, but was a potent inducer of aneuploidy and chromosomal instability. We determined that NUP88 and the nuclear transport factors NUP98 and RAE1 comprise a regulatory network that inhibits premitotic activity of the anaphase-promoting complex/cyclosome (APC/C). When overexpressed, NUP88 sequesters NUP98-RAE1 away from APC/C-CDH1, triggering proteolysis of polo-like kinase 1 (PLK1), a tumor suppressor and multitasking mitotic kinase. Premitotic destruction of PLK1 disrupts centrosome separation, causing mitotic spindle asymmetry, merotelic microtubule-kinetochore attachments, lagging chromosomes, and aneuploidy. These effects were replicated by PLK1 insufficiency, indicating that PLK1 is responsible for the mitotic defects associated with NUP88 overexpression. These findings demonstrate that the NUP88-NUP98-RAE1-APC/C-CDH1 axis contributes to aneuploidy and suggest that it may be deregulated in the initiating stages of a broad spectrum of human cancers.