CREB Binding Protein Interacts with Nucleoporin-Specific FG Repeats That Activate Transcription and Mediate NUP98-HOXA9 Oncogenicity
CREB Binding Protein Interacts with Nucleoporin-Specific FG Repeats That Activate Transcription and Mediate NUP98-HOXA9 Oncogenicity
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DOI：
10.1128/mcb.19.1.764
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发表时间：
1999-01
影响因子：
5.3
通讯作者：
L. Kasper;Paul K. Brindle;C. Schnabel;C. Pritchard;M. Cleary;J. V. van Deursen
中科院分区：
文献类型：
--
作者：
L. Kasper;Paul K. Brindle;C. Schnabel;C. Pritchard;M. Cleary;J. V. van Deursen
编码含Phe-Gly（FG）重复序列的核孔蛋白NUP 98和CAN/NUP 214的基因位于与人类急性髓性白血病（AML）相关的几种染色体易位的断点上，但它们在肿瘤发生中的作用尚不清楚。在这里，我们证明了NUP 98-HOXA 9融合基因编码两个核癌蛋白与19或37 NUP 98 FG重复融合的DNA结合和PBX异源二聚化结构域的转录因子HOXA 9。NUP 98-HOXA 9嵌合体都转化了NIH 3 T3成纤维细胞，这种转化需要HOXA 9结构域进行DNA结合和PBX相互作用。令人惊讶的是，FG重复作为非常有效的基因转录的反式激活因子。这种NUP 98衍生的活性对于转化是必需的，并且可以被VP 16的真正的反式激活结构域所取代。有趣的是，来自核孔蛋白NUP 153和CAN/NUP 214的含有FG重复的片段与来自NUP 98的片段功能相似。我们进一步证明，反式激活的FG重复丰富的NUP 98片段与他们的能力，相互作用的功能和物理的转录辅激活因子CREB结合蛋白（CBP）和p300。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，我们的研究结果表明，NUP 98-HOXA 9嵌合体是异常的转录因子，通过招募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应答基因的调节。事实上，FG重复介导的反式激活可能是涉及人类AML的核孔蛋白的共同致病功能。
ABSTRACT 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.