Forced expression of the DEK-NUP214 fusion protein promotes proliferation dependent on upregulation of mTOR.
Forced expression of the DEK-NUP214 fusion protein promotes proliferation dependent on upregulation of mTOR.
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DOI：
10.1186/1471-2407-13-440
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发表时间：
2013-09-27
期刊：
影响因子：
3.8
通讯作者：
Gullberg U
中科院分区：
文献类型：
--
作者：
Sandén C;Ageberg M;Petersson J;Lennartsson A;Gullberg U
t（6; 9）（p23; q34）染色体易位在1%的急性髓性白血病中被发现，并编码融合蛋白DEK-NUP 214（以前称为DEK-CAN），其功能在很大程度上未被表征。我们在骨髓细胞系U937和PL-21中表达DEK-NUP 214，并研究了对细胞功能的影响。在这项研究中，我们证明了DEK-NUP 214的表达增加了细胞增殖。蛋白质印迹分析显示，调节增殖的关键蛋白之一，雷帕霉素的机制靶点mTOR的水平升高。这赋予了mTORC 1而不是mTORC 2活性的增加，如通过其底物p70 S6激酶和Akt的磷酸化所确定的。mTOR上调的功能重要性通过测定下游细胞过程来确定;蛋白质合成和葡萄糖代谢。整体翻译试验显示翻译速率大幅增加，代谢试验检测到从糖酵解到氧化磷酸化的转变，如通过乳酸盐产生减少而葡萄糖消耗没有伴随减少所确定的。这两种效应都与mTORC 1活性增加一致。用mTORC 1抑制剂依维莫司（RAD 001）治疗选择性逆转了DEK-NUP 214诱导的增殖，表明该作用是mTOR依赖性的。我们的研究表明，DEK-NUP 214融合基因通过上调mTOR增加增殖，这表明携带DEK-NUP 214的白血病患者可能受益于mTOR抑制剂的治疗。
The t(6;9)(p23;q34) chromosomal translocation is found in 1% of acute myeloid leukemia and encodes the fusion protein DEK-NUP214 (formerly DEK-CAN) with largely uncharacterized functions. We expressed DEK-NUP214 in the myeloid cell lines U937 and PL-21 and studied the effects on cellular functions. In this study, we demonstrate that expression of DEK-NUP214 increases cellular proliferation. Western blot analysis revealed elevated levels of one of the key proteins regulating proliferation, the mechanistic target of rapamycin, mTOR. This conferred increased mTORC1 but not mTORC2 activity, as determined by the phosphorylation of their substrates, p70 S6 kinase and Akt. The functional importance of the mTOR upregulation was determined by assaying the downstream cellular processes; protein synthesis and glucose metabolism. A global translation assay revealed a substantial increase in the translation rate and a metabolic assay detected a shift from glycolysis to oxidative phosphorylation, as determined by a reduction in lactate production without a concomitant decrease in glucose consumption. Both these effects are in concordance with increased mTORC1 activity. Treatment with the mTORC1 inhibitor everolimus (RAD001) selectively reversed the DEK-NUP214-induced proliferation, demonstrating that the effect is mTOR-dependent. Our study shows that the DEK-NUP214 fusion gene increases proliferation by upregulation of mTOR, suggesting that patients with leukemias carrying DEK-NUP214 may benefit from treatment with mTOR inhibitors.
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