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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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 1

NUP88 overexpression drives tumorigenesis.

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NUP88 overexpression drives tumorigenesis. (A) Representative images of ...
(A) Representative images of MEFs immunostained for HA and NUP88. Fixation with PFA was optimized for the NE (5 minutes in 1% PFA) or the entire cell (15 minutes in 3% PFA). (B) Western blot analysis of lung and colon tissue lysates from 6-week-old dox-treated HA-Nup88 and control (TA) transgenic mice. Ponceau S (PonS) staining of blotted proteins served as a loading control. (C) Spontaneous tumor incidence in 14-month-old transgenic mice. Sample sizes of 24 TA and 25 Nup88T mice were used. (D) Spectrum of spontaneous tumor types observed. HCA, hepatocellular adenoma; HCC, hepatocellular carcinoma. (E) Representative gross and histological images of lung adenomas from 14-month-old transgenic mice. (F) Representative gross images of colon tumors from TA APC+/Min and Nup88T11 APC+/Min mice. (G) Colon tumor incidence, (H) multiplicity, and (I) mean colon tumor size in TA APC+/Min and Nup88T11 APC+/Min mice. Sample sizes of 20 TA APC+/Min (90 d +dox), 24 Nup88T11 APC+/Min (90 d +dox), and 17 Nup88T11 APC+/Min (60 d +dox, 30 d −dox) mice were used. Data represent the mean ± SEM. Western blots are representative of 3 independent experiments. Statistical significance was determined using a 2-sided Fisher’s exact test (C and D) and a 1-sided Fisher’s exact test with Bonferroni’s correction (G). *P < 0.05 and **P < 0.01. Scale bars: 10 μm (A), 1 mm (E and F). Nup88T indicates combined transgenic lines 11 and 13.