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首页> 外文期刊>Cell cycle >The C-terminal domains of human neurofibromin and its budding yeast homologs Ira1 and Ira2 regulate the metaphase to anaphase transition
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The C-terminal domains of human neurofibromin and its budding yeast homologs Ira1 and Ira2 regulate the metaphase to anaphase transition

机译：人神经纤维蛋白的C末端结构域及其萌芽的酵母同源物Ira1和Ira2调节中期到后期的过渡

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摘要

The human tumor suppressor neurofibromin contains a cysteine and serine-rich domain/Ras-GTPase activating protein domain (CSRD/RasGAP) and a C-terminal domain (CTD). Domain studies of neurofibromin suggest it has other functions in addition to being a RasGAP, but the mechanisms underlying its tumor suppressor activity are not well understood. The budding yeast Saccharomyces cerevisiae is a good model system for studying neurofibromin function because it possesses Ira1 and Ira2, which are homologous to human neurofibromin in both sequence and function. We found that overexpression of CTD or a neurofibromin CTD-homologous domain (CHD) of Ira1/2 in budding yeast delayed degradation of the securin protein Pds1, whereas overexpression of CSRD/RasGAP did not affect Pds1 degradation. We also found that when CTD or CHD was overexpressed, the number of cells in metaphase was higher than in the control. These results demonstrate that CTD and CHD function in the metaphase to anaphase transition. In addition, Δira1Δira2 cells bypassed mitotic arrest in response to spindle damage, indicating that Ira1 and Ira2 may be involved in the spindle assembly checkpoint (SAC). However, Δira1Δira2Δmad2 cells are more sensitive to spindle damage than Δmad2 or Δira1Δira2 cells are, suggesting that Ira1/2 and Mad2 function in different pathways. Overexpression of CTD but not CSRD/RasGAP partially rescued the hypersensitivity of Dira1Dira2Dmad2 cells to microtubule-destabilizing drugs, indicating a role for CTD in the SAC pathway. Taken together, independently of RasGAP activity, the C-terminal domains of neurofibromin, Ira1, and Ira2 regulate the metaphase to anaphase transition in a Mad2-independent fashion.
机译：人肿瘤抑制神经纤维蛋白含有半胱氨酸和富含丝氨酸的结构域/ Ras-GTP酶激活蛋白结构域（CSRD / RasGAP）和C端结构域（CTD）。神经纤维蛋白的领域研究表明，它除了是RasGAP以外，还具有其他功能，但是其肿瘤抑制活性的机制尚不清楚。出芽的酿酒酵母是研究神经纤维蛋白功能的良好模型系统，因为它具有Ira1和Ira2，它们在序列和功能上均与人神经纤维蛋白同源。我们发现在发芽酵母中CTD或Ira1 / 2的神经纤维蛋白CTD同源域（CHD）的过表达延迟了securin蛋白Pds1的降解，而CSRD / RasGAP的过表达并不影响Pds1的降解。我们还发现，当CTD或CHD过表达时，中期细胞数高于对照组。这些结果证明CTD和CHD在中期到后期的转变中起作用。此外，响应于纺锤体损伤，Δira1Δira2细胞绕过了有丝分裂阻滞，表明Ira1和Ira2可能参与纺锤体装配检查点（SAC）。但是，Δira1Δira2Δmad2细胞比Δmad2或Δira1Δira2细胞对纺锤体损伤更敏感，这表明Ira1 / 2和Mad2在不同的途径中起作用。 CTD的过度表达而非CSRD / RasGAP的过度表达部分挽救了Dira1Dira2Dmad2细胞对微管破坏性药物的超敏性，表明CTD在SAC途径中的作用。总之，独立于RasGAP活性，神经纤维蛋白，Ira1和Ira2的C末端结构域以Mad2独立的方式调节中期到后期的过渡。

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