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首页> 外文期刊>Molecular and Cellular Pharmacology >The Immunosuppressant FTY720 (Fingolimod) Induces Nuclear Exit of the Proto-oncogene SET/I2PP2A
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The Immunosuppressant FTY720 (Fingolimod) Induces Nuclear Exit of the Proto-oncogene SET/I2PP2A

机译：免疫抑制剂FTY720（芬戈莫德）诱导原癌基因SET / I2PP2A的核退出

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The proto-oncogene SET/I2PP2A, an inhibitor of the phosphatase PP2A and a potential therapeutic target for cancer, interacts with the RhoGTPase Rac1 and regulates cell motility. SET is primarily nuclear but can readily translocate to the cytoplasm. Here, we investigated this translocation in more detail. Using an image analysis method to analyse nucleo-cytoplasmic shuttling of YFP-SET, we find that the protein shows repetitive shuttling in a seemingly random fashion. We found that Rac1 activity increases the frequency of these nuclear exit events of SET. In search for cellular activators of this event, we found FTY720 (fingolimod), an immunomodulator and activator of PP2A, to rapidly induce nucleo-cytoplasmic translocation of SET. Subsequently, SET accumulates in cytoplasmic aggregates of unknown nature. Moreover, we observed that the nuclear pool of Rac1 translocates simultaneously with SET, both during spontaneous as well as FTY720-induced translocation. Finally, FTY720-induced nuclear exit is dependent on the nuclear exporter CRM1, on PP2A activity as well as on microtubule dynamics. These results show that the immunomodulator and PP2A activator FTY720, induces rapid nucleo-cytoplasmic shuttling of SET, suggesting that SET translocation is part of a negative feedback loop. This data may be relevant to the potential use of FTY720 in the treatment of leukemias and inflammatory disorders.
机译：原癌基因SET / I2PP2A是磷酸酶PP2A的抑制剂，也是癌症的潜在治疗靶标，它与RhoGTPase Rac1相互作用并调节细胞运动。 SET主要是​​核的，但是可以容易地转移到细胞质。在这里，我们更详细地研究了这种易位。使用图像分析方法分析YFP-SET的核质穿梭，我们发现该蛋白以看似随机的方式显示出重复穿梭。我们发现Rac1活性增加SET的这些核出口事件的频率。在寻找此事件的细胞激活剂时，我们发现FTY720（芬戈莫德）是PP2A的免疫调节剂和激活剂，可快速诱导SET的核质易位。随后，SET在未知性质的细胞质聚集物中积累。此外，我们观察到Rac1的核库与SET同时移位，无论是在自发还是FTY720诱导的移位期间。最后，FTY720诱导的核出口取决于核出口者CRM1，PP2A活性以及微管动力学。这些结果表明免疫调节剂和PP2A激活剂FTY720诱导SET的快速核质穿梭，表明SET易位是负反馈环的一部分。该数据可能与FTY720在白血病和炎性疾病治疗中的潜在用途有关。

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