American Association for Cancer Research
00085472can130912-sup-fig_2.pdf (1.42 MB)

Supplementary Figure 2 from NUP98 Fusion Oncoproteins Promote Aneuploidy by Attenuating the Mitotic Spindle Checkpoint

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journal contribution
posted on 2023-03-30, 22:32 authored by Valentina Salsi, Silvia Ferrari, Paolo Gorello, Sebastian Fantini, Francesca Chiavolelli, Cristina Mecucci, Vincenzo Zappavigna

PDF - 1450K, Supplementary Figure 2. Proteasome inhibition rescues NUP98-fusions effects on Securin and Cyclin B degradation. Western blot analysis showing securin (SEC) and cyclin B (CCNB1) levels in HEK293 cells transfected with the indicated constructs after treatment with Nocodazole or Nocodazole and the proteasome inhibitor MG132 for 24 hours. An increase of CCNB1 levels can be appreciated in control cells following MG132 treatment as the result of efficient proteasome inactivation. Anti-betaactin antibody (betaACT) was used as a loading control.



NUP98 is a recurrent fusion partner in chromosome translocations that cause acute myelogenous leukemia. NUP98, a nucleoporin, and its interaction partner Rae1, have been implicated in the control of chromosome segregation, but their mechanistic contributions to tumorigenesis have been unclear. Here, we show that expression of NUP98 fusion oncoproteins causes mitotic spindle defects and chromosome missegregation, correlating with the capability of NUP98 fusions to cause premature securin degradation and slippage from an unsatisfied spindle assembly checkpoint (SAC). NUP98 fusions, unlike wild-type NUP98, were found to physically interact with the anaphase promoting complex/cyclosome (APC/C)Cdc20 and to displace the BubR1 SAC component, suggesting a possible mechanistic basis for their interference with SAC function. In addition, NUP98 oncoproteins displayed a prolonged half-life in cells. We found that NUP98 stability is controlled by a PEST sequence, absent in NUP98 oncoproteins, whose deletion reproduced the aberrant SAC-interfering activity of NUP98 oncoproteins. Together, our findings suggest that NUP98 oncoproteins predispose myeloid cells to oncogenic transformation or malignant progression by promoting whole chromosome instability. Cancer Res; 74(4); 1079–90. ©2013 AACR.

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