Genistein induces topoisomerase IIbeta- and proteasome-mediated DNA sequence rearrangements: Implications in infant leukemia
Genistein induces topoisomerase IIbeta- and proteasome-mediated DNA sequence rearrangements: Implications in infant leukemia
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DOI：
10.1016/j.bbrc.2010.07.043
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发表时间：
2010-08-13
影响因子：
3.1
通讯作者：
Lyu, Yi Lisa
中科院分区：
文献类型：
--
作者：
Azarova, Anna M.;Lin, Ren-Kuo;Lyu, Yi Lisa
染料木黄酮是一种富含大豆制品的生物素。然而，母亲高水平的大豆消费与婴儿白血病ALL和AML的发展有关。大多数婴儿白血病与混合系白血病基因（MLL）易位有关。先前的研究表明拓扑异构酶II（Top2）与染料木素诱导的婴儿白血病有关。为了了解两种Top2同工酶在染料木素诱导的婴儿白血病中的作用及其分子机制，我们使用纯化的重组人Top2同工酶进行了体外研究，以及在培养的小鼠骨髓祖细胞（32 Dc 13）和Top2 β敲除小鼠胚胎成纤维细胞（MEFs）中的研究。首先，我们表明，染料木黄酮有效地诱导Top2 α和Top2 β裂解复合物在纯化的系统，以及在培养的小鼠细胞。第二，染料木黄酮诱导32 Dc 13细胞中Top2 β的蛋白酶体降解。第三，染料木素诱导的DNA双链断裂（DSB）信号，γ-H2 AX，依赖于Top2 β同工酶和蛋白酶体活性。第四，Top2 β和蛋白酶体活性的要求反映在染料木素诱导的DNA序列重排，通过DNA整合试验监测。总之，我们的研究结果表明，一个模型中，染料木素诱导的Top2 β裂解复合物被蛋白酶体处理，导致暴露，否则Top2 β隐藏的DSB和随后的染色体重排，并牵连的主要作用Top2 β和蛋白酶体在染料木素诱导的婴儿白血病。(C)2010年爱思唯尔公司All rights reserved.
Genistein is a bioflavonoid enriched in soy products. However, high levels of maternal soy consumption have been linked to the development of infant leukemia ALL and AML The majority of infant leukemia is linked to mixed lineage leukemia gene (MLL) translocations. Previous studies have implicated topoisomerase II (Top2) in genistein-induced infant leukemia. In order to understand the roles of the two Top2 isozymes in and the molecular mechanism for genistein-induced infant leukemia, we carried out studies in vitro using purified recombinant human Top2 isozymes, as well as studies in cultured mouse myeloid progenitor cells (32Dc13) and Top2 beta knockout mouse embryonic fibroblasts (MEFs). First, we showed that genistein efficiently induced both Top2 alpha and Top2 beta cleavage complexes in the purified system as well as in cultured mouse cells. Second, genistein induced proteasomal degradation of Top2 beta in 32Dc13 cells. Third, the genistein-induced DNA double-strand break (DSB) signal, gamma-H2AX, was dependent on the Top2 beta isozyme and proteasome activity. Fourth, the requirement for Top2 beta and proteasome activity was mirrored in genistein-induced DNA sequence rearrangements, as monitored by a DNA integration assay. Together, our results suggest a model in which genistein-induced Top2 beta cleavage complexes are processed by proteasome, leading to the exposure of otherwise Top2 beta-concealed DSBs and subsequent chromosome rearrangements, and implicate a major role of Top2 beta and proteasome in genistein-induced infant leukemia. (C) 2010 Elsevier Inc. All rights reserved.