Decreased intranuclear mobility of acute myeloid leukemia 1-containing fusion proteins is accompanied by reduced mobility and compartmentalization of core binding factor beta.
Decreased intranuclear mobility of acute myeloid leukemia 1-containing fusion proteins is accompanied by reduced mobility and compartmentalization of core binding factor beta.
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含有急性髓系白血病 1 的融合蛋白的核内迁移率降低伴随着核心结合因子 β 的迁移率和区室化的降低。
DOI：
10.1038/sj.onc.1209431
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发表时间：
2006
期刊：
影响因子：
--
通讯作者：
Dong,S
中科院分区：
文献类型：
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作者：
Qiu,J;Wong,J;Tweardy,DJ;Dong,S
21号染色体上的急性髓性白血病1 （AML1）基因参与了包括t（8; 21）和t（16; 21）在内的几种染色体易位，产生嵌合融合蛋白AML1 - 821 （ETO）和aml -髓性转化基因16号染色体（MTG16），从而促进白血病的发生。这些融合蛋白致白血病作用的分子基础尚不完全清楚。通过凝胶转移实验，我们发现AML1 - eto和AML1 - mtg16结合在一系列AML1一致的dna结合位点上，具有不同的亲和力。利用光漂白后荧光恢复（FRAP），我们证明与野生型AML1或任何融合伙伴相比，与ETO或MTG16融合的AML1表现出更低的核内迁移率。ETO的二聚化结构域（神经同源区2）是AML1-ETO迁移率降低的原因。双重FRAP研究表明，CBFβ在细胞核内与AML1-ETO共定位，导致CBFβ的移动性降低。因此，由于异常的核动力学，AML1融合蛋白可能会干扰正常的AML1功能，从而导致CBFβ和其他对髓细胞分化至关重要的共调节因子在空间和时间上的隔离。
Acute myeloid leukemia 1 (AML1) gene on chromosome 21 is involved in several chromosomal translocations, including t (8; 21) and t (16; 21), that produce chimeric fusion proteins AML1–eight twenty-one (ETO) and AML–myeloid transforming gene chromosome 16 (MTG16), which contribute to leukemogenesis. The molecular basis for the leukemogenic effects of these fusion proteins is incompletely understood. Using gel-shift assay, we showed that AML1–ETO and AML1–MTG16 bound to a series of AML1 consensus DNA-binding sites with different affinities. Using fluorescence recovery after photobleaching (FRAP), we demonstrated that a fusion of AML1 with ETO or MTG16 exhibits reduced intranuclear mobility compared with wild-type AML1 or either fusion partner. The dimerization domain (nervy homology region 2) of ETO is responsible for the reduced mobility of AML1–ETO. Dual FRAP studies revealed that CBFβ colocalized with AML1–ETO within the nucleus, resulting in reduced mobility of CBFβ. Therefore, AML1 fusion proteins may interfere with normal AML1 function due to aberrant nuclear dynamics, which leads to spatial and temporal sequestration of CBFβ and perhaps other coregulators critical for myeloid differentiation.