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首页> 外文期刊>Molecular and Cellular Biology >Reduced Intranuclear Mobility of APL Fusion Proteins Accompanies Their Mislocalization and Results in Sequestration and Decreased Mobility of Retinoid X Receptor α
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Reduced Intranuclear Mobility of APL Fusion Proteins Accompanies Their Mislocalization and Results in Sequestration and Decreased Mobility of Retinoid X Receptor α

机译：APL融合蛋白的核内迁移减少，并伴随错误定位，并导致类维生素A X受体α的螯合和迁移减少

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Acute promyelocytic leukemia (APL) cells contain one of five chimeric retinoic acid α-receptor (RARα) genes (X-RARα) created by chromosomal translocations or deletion; each generates a fusion protein thought to transcriptionally repress RARα target genes and block myeloid differentiation by an incompletely understood mechanism. To gain spatiotemporal insight into these oncogenic processes, we employed fluorescence microscopy and fluorescence recovery after photobleaching (FRAP). Fluorescence microscopy demonstrated that the intracellular localization of each of the X-RARα proteins was distinct from that of RARα and established which portion(s) of each X-RARα protein—X, RAR, or both—contributed to its altered localization. Using FRAP, we demonstrated that the intranuclear mobility of each X-RARα was reduced compared to that of RARα. In addition, the mobility of each X-RARα was reduced further by ligand addition, in contrast to RARα, which showed no change in mobility when ligand was added. Both the reduced baseline mobility of X-RARα and the ligand-induced slowing of X-RARα could be attributed to the protein interaction domain contained within X. RXRα aberrantly colocalized within each X-RARα; colocalization of RXRα with promyelocytic leukemia (PML)-RARα resulted in reduced mobility of RXRα. Thus, X-RARα may interfere with RARα through its aberrant nuclear dynamics, resulting in spatial and temporal sequestration of RXRα and perhaps other nuclear receptor coregulators critical for myeloid differentiation.
机译：急性早幼粒细胞白血病（APL）细胞包含通过染色体易位或缺失产生的五个嵌合视黄酸α-受体（RARα）基因（X-RARα）之一;每一种都产生一种融合蛋白，该蛋白被认为可以通过转录抑制RARα靶基因，并通过一种不完全了解的机制阻止髓样分化。为了获得对这些致癌过程的时空洞察力，我们采用了荧光显微镜和光漂白后的荧光恢复（FRAP）。荧光显微镜检查表明，每种X-RARα蛋白的细胞内定位均不同于RARα的细胞内定位，并确定了每种X-RARα蛋白的哪个部分（X，RAR或两者）导致其定位改变。使用FRAP，我们证明了每个X-RARα的核内迁移率均低于RARα。另外，与RARα相反，通过添加配体进一步降低了每个X-RARα的迁移率，RARα在添加配体时没有显示出迁移率的变化。 X-RARα的基线迁移率降低和配体诱导的X-RARα减慢都可以归因于X中包含的蛋白质相互作用域。RXRα在每个X-RARα中异常共定位; RXRα与早幼粒细胞白血病（PML）-RARα的共定位导致RXRα的活动性降低。因此，X-RARα可能通过其异常的核动力学干扰RARα，导致RXRα以及可能对髓样分化至关重要的其他核受体共调节剂的空间和时间隔离。

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