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首页> 外文期刊>Molecular and Cellular Biology >CREB Binding Protein Interacts with Nucleoporin-Specific FG Repeats That Activate Transcription and Mediate NUP98-HOXA9 Oncogenicity
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CREB Binding Protein Interacts with Nucleoporin-Specific FG Repeats That Activate Transcription and Mediate NUP98-HOXA9 Oncogenicity

机译：CREB结合蛋白与核蛋白特异性FG重复序列相互作用，激活转录并介导NUP98-HOXA9致癌性。

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Genes encoding the Phe-Gly (FG) repeat-containing nucleoporins NUP98 and CAN/NUP214 are at the breakpoints of several chromosomal translocations associated with human acute myeloid leukemia (AML), but their role in oncogenesis is unclear. Here we demonstrate that the NUP98-HOXA9 fusion gene encodes two nuclear oncoproteins with either 19 or 37 NUP98 FG repeats fused to the DNA binding and PBX heterodimerization domains of the transcription factor HOXA9. Both NUP98-HOXA9 chimeras transformed NIH 3T3 fibroblasts, and this transformation required the HOXA9 domains for DNA binding and PBX interaction. Surprisingly, the FG repeats acted as very potent transactivators of gene transcription. This NUP98-derived activity is essential for transformation and can be replaced by the bona fide transactivation domain of VP16. Interestingly, FG repeat-containing segments derived from the nucleoporins NUP153 and CAN/NUP214 functioned similarly to those from NUP98. We further demonstrate that transactivation by FG repeat-rich segments of NUP98 correlates with their ability to interact functionally and physically with the transcriptional coactivators CREB binding protein (CBP) and p300. This finding shows, for the first time, that a translocation-generated fusion protein appears to recruit CBP/p300 as an important step of its oncogenic mechanism. Together, our results suggest that NUP98-HOXA9 chimeras are aberrant transcription factors that deregulate HOX-responsive genes through the transcriptional activation properties of nucleoporin-specific FG repeats that recruit CBP/p300. Indeed, FG repeat-mediated transactivation may be a shared pathogenic function of nucleoporins implicated human AML.
机译：编码含有Phe-Gly（FG）重复序列的核孔蛋白NUP98和CAN / NUP214的基因位于与人类急性髓细胞性白血病（AML）相关的几个染色体易位的转折点，但尚不清楚它们在肿瘤发生中的作用。在这里，我们证明 NUP98-HOXA9 融合基因编码两个核癌蛋白，其中19个或37个NUP98 FG重复序列与转录因子HOXA9的DNA结合和PBX异二聚结构域融合。 NUP98-HOXA9嵌合体均转化了NIH 3T3成纤维细胞，这种转化需要HOXA9域进行DNA结合和PBX相互作用。出人意料的是，FG重复序列是非常有效的基因转录反式激活因子。 NUP98衍生的活性对于转化至关重要，可以被VP16的真正反式激活结构域取代。有趣的是，衍生自核孔蛋白NUP153和CAN / NUP214的含有FG重复序列的片段的功能与NUP98相似。我们进一步证明，NUP98的富含FG重复序列的区段的反式激活与其与转录共激活因子CREB结合蛋白（CBP）和p300在功能上和物理上相互作用的能力有关。这一发现首次表明，易位产生的融合蛋白似乎招募CBP / p300作为其致癌机制的重要步骤。总之，我们的结果表明NUP98-HOXA9嵌合体是异常的转录因子，通过募集CBP / p300的核孔蛋白特异性FG重复序列的转录激活特性来解除HOX响应基因的调控。实际上，FG重复介导的反式激活可能是核孔蛋白与人类AML相关的共同致病功能。

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