Nuclear pore protein NUP88 activates anaphase-promoting complex to promote aneuploidy
Ryan M. Naylor, … , Xiuqi Cao, Jan M. van Deursen
Ryan M. Naylor, … , Xiuqi Cao, Jan M. van Deursen
Published January 5, 2016
Citation Information: J Clin Invest. 2016;126(2):543-559. https://doi.org/10.1172/JCI82277.
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Research Article Oncology

Nuclear pore protein NUP88 activates anaphase-promoting complex to promote aneuploidy

Abstract

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/CCDH1, 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/CCDH1 axis contributes to aneuploidy and suggest that it may be deregulated in the initiating stages of a broad spectrum of human cancers.

Authors

Ryan M. Naylor, Karthik B. Jeganathan, Xiuqi Cao, Jan M. van Deursen

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Figure 8

Perturbation of the NUP88-NUP98-RAE1 axis blocks separase activity via PLK1 insufficiency.

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Perturbation of the NUP88-NUP98-RAE1 axis blocks separase activity via P...
(A) Schematic representation of the separase biosensor used for live-cell–imaging experiments. (B) Representative images of Nup88T MEFs expressing the separase biosensor before and after anaphase onset. (C) Quantification of biosensor cleavage for cells in B as they progressed through mitosis. (D) Representative images of Nup98+/− Rae1+/− MEFs expressing the separase biosensor before and after anaphase onset. (E) Quantification of biosensor cleavage for cells in D as they progressed through mitosis. (F) Representative images of WT MEFs transduced with Plk1 shRNA no. 1 expressing the separase biosensor before and after anaphase onset. (G) Quantification of biosensor cleavage for cells in F as they progressed through mitosis. Analyses in C, E, and G were performed on at least 10 cells per genotype from 2 independent lines. Data represent the mean ± SEM. Statistical significance at anaphase onset (T = 0 h) of mutant chromatin bridges versus control normal anaphases in C, E, and G was determined using a 1-way ANOVA, followed by Tukey’s multiple comparisons test. *P < 0.05 and **P < 0.01. Scale bars: 10 μm. Nup88T indicates the combined transgenic lines 11 and 13.