The t(5;17) acute promyelocytic leukemia fusion protein NPM-RAR interacts with co-repressor and co-activator proteins and exhibits both positive and negative transcriptional properties.
The t(5;17) acute promyelocytic leukemia fusion protein NPM-RAR interacts with co-repressor and co-activator proteins and exhibits both positive and negative transcriptional properties.
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DOI：
10.1182/blood.v95.8.2683
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发表时间：
2000-04
期刊：
影响因子：
20.3
通讯作者：
R. Redner;J. Chen;E. Rush;Hui Li;Sheri L. Pollock
中科院分区：
文献类型：
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作者：
R. Redner;J. Chen;E. Rush;Hui Li;Sheri L. Pollock
急性早幼粒细胞白血病（APL）的t（5;17）变异融合了核磷蛋白（NPM）和视黄酸受体α (rar α)的基因。两个NPM-RAR分子的表达是选择性RNA剪接的结果。两者都含有rar α序列，编码rar α的DNA结合、异源二聚化和配体激活域。本研究旨在测试这些融合蛋白作为维甲酸应答启动子的转录激活剂的能力。NPM-RAR融合蛋白以RXR的同二聚体或异二聚体结合维甲酸反应元件序列。视黄酸诱导启动子的转录在视黄酸存在下被融合蛋白激活。NPM-RAR融合诱导的转激活水平在启动子和细胞特异性方面不同于野生型rar α诱导的转激活水平，并且与野生型rar α相比，ppm - rar融合的激活模式更接近。此外，当NPM-RAR与野生型rar α共转染时，NPM-RAR减少了一些启动子的基础转录，并以显性阴性方式发挥作用。NPM-RAR和PML-RAR与共抑制蛋白SMRTe相互作用的方式对视黄酸解离的敏感性低于rar α。维甲酸诱导共激活蛋白RAC3的结合。这些数据表明，NPM-RAR融合蛋白可以根据启动子的背景，以积极或消极的方式调节类视黄醇反应基因的表达，并支持异常转录激活是APL表型基础的假设。(血。2000;95:2683 - 2690)
The t(5;17) variant of acute promyelocytic leukemia (APL) fuses the genes for nucleophosmin (NPM) and the retinoic acid receptor alpha (RARalpha). Two NPM-RAR molecules are expressed as a result of alternative RNA splicing. Both contain RARalpha sequences that encode the DNA binding, heterodimerization, and ligand activation domains of RARalpha. This study was designed to test the ability of these fusion proteins to act as transcriptional activators of retinoic acid responsive promoters. The NPM-RAR fusion proteins bind to retinoic acid response element sequences as either homodimers or as heterodimers with RXR. Transcription of retinoic acid-inducible promoters is activated by the fusion proteins in the presence of retinoic acid. The level of transactivation induced by the NPM-RAR fusions differs from the level of transactivation induced by wild-type RARalpha in both a promoter and cell specific fashion, and more closely parallels the pattern of activation of the PML-RAR fusion than wild-type RARalpha. In addition, NPM-RAR decreases basal transcription from some promoters and acts in a dominant-negative fashion when co-transfected with wild-type RARalpha. Both NPM-RAR and PML-RAR interact with the co-repressor protein SMRTe in a manner that is less sensitive than RARalpha to dissociation by retinoic acid. Retinoic acid induces binding of the co-activator protein RAC3. These data indicate that the NPM-RAR fusion proteins can modulate expression of retinoid-responsive genes in a positive or negative manner, depending on context of the promoter, and lend support to the hypothesis that aberrant transcriptional activation underlies the APL phenotype. (Blood. 2000;95:2683-2690)