Authors' Affiliations: Department of Life Sciences, University of Modena and Reggio Emilia, Modena; and Department of Hematology, University of Perugia, University Hospital S. Maria della Misericordia, Perugia, Italy.
Cancer Res. 2014 Feb 15;74(4):1079-90. doi: 10.1158/0008-5472.CAN-13-0912. Epub 2013 Dec 26.
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.
NUP98 是导致急性髓系白血病的染色体易位中反复出现的融合伙伴。核孔蛋白 NUP98 及其相互作用伙伴 Rae1 被认为参与了染色体分离的控制，但它们在肿瘤发生中的机制贡献尚不清楚。在这里，我们表明 NUP98 融合癌蛋白的表达会导致有丝分裂纺锤体缺陷和染色体错误分离，这与 NUP98 融合导致早熟 securin 降解和从未满足的纺锤体装配检查点 (SAC) 滑动的能力有关。与野生型 NUP98 不同，NUP98 融合被发现与后期促进复合物/环体 (APC/C)(Cdc20) 发生物理相互作用，并取代 SAC 成分 BubR1，这表明它们干扰 SAC 功能的可能机制基础。此外，NUP98 癌蛋白在细胞中的半衰期延长。我们发现 NUP98 的稳定性受 PEST 序列的控制，而 NUP98 癌蛋白中不存在该序列，其缺失复制了 NUP98 癌蛋白异常的 SAC 干扰活性。总之，我们的发现表明，NUP98 癌蛋白通过促进全染色体不稳定性，使髓系细胞易发生致癌转化或恶性进展。
