Nuclear pore protein NUP88 activates anaphase-promoting complex to promote aneuploidy
Ryan M. Naylor, Karthik B. Jeganathan, Xiuqi Cao, Jan M. van Deursen
Ryan M. Naylor, Karthik B. Jeganathan, Xiuqi Cao, Jan M. van Deursen
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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 3

NUP98-RAE1 protects de novo synthesized securin from APC/CCDH1-mediated degradation in the G2 phase, and NUP88 overexpression perturbs this protective mechanism.

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NUP98-RAE1 protects de novo synthesized securin from APC/CCDH1-mediated ...
(A) Images of G2-phase MEFs of the indicated genotypes transduced with a lentivirus expressing securin-EYFP. (B) Quantification of securin-EYFP intensity in MEFs from A progressing from G2 through mitosis. (C) Strategy for G2-phase synchronization in MEFs. See Methods for more information. (D) Western blot analysis of Nup88T MEFs synchronized in G2 in the presence or absence of MG132. (E) Western blot analysis of Nup98+/− Rae1+/− MEFs synchronized in G2 in the presence or absence of MG132. (F) Images of interphase Nup88T MEFs expressing securin-EYFP before and after 1 hour of MG132 treatment. (G) Quantification of securin-EYFP intensity in MEFs from F treated with MG132, proTAME, or apcin. (H) Representative images of interphase Nup98+/− Rae1+/− MEFs expressing securin-EYFP before and after 1 hour of MG132 treatment. (I) Quantification of securin-EYFP intensity in MEFs from H treated with MG132, proTAME, or apcin. Analyses in B, G, and I were performed on 3 independent lines per genotype (>8 cells/line). Data represent the mean ± SEM. Western blots are representative of 3 independent experiments. Statistical significance in G and I was determined using a 2-tailed, unpaired t test. *P < 0.05 and **P < 0.01. Scale bars: 10 μm. Nup88T indicates the combined transgenic lines 11 and 13.