Transcriptional regulation of the proto-oncogene Zfp521 by SPI1 (PU.1) and HOXC13.
Transcriptional regulation of the proto-oncogene Zfp521 by SPI1 (PU.1) and HOXC13.
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DOI：
10.1002/dvg.22963
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发表时间：
2016-10
期刊：
影响因子：
1.5
通讯作者：
Hentges, Kathryn E.
中科院分区：
文献类型：
--
作者：
Yu, Ming;Al-Dallal, Salma;Al-Haj, Latifa;Panjwani, Shiraj;McCartney, Akina S.;Edwards, Sarah M.;Manjunath, Pooja;Walker, Catherine;Awgulewitsch, Alexander;Hentges, Kathryn E.
小鼠锌指基因Zfp 521（也称为亲嗜性病毒插入位点3; Evi 3;和人类ZNF 521）已被鉴定为B细胞原癌基因，在其启动子区域插入逆转录病毒后导致小鼠白血病，驱动Zfp 521过表达。此外，ZNF 521在人类造血细胞中表达，ZNF 521和PAX 5之间的易位与儿科急性淋巴细胞白血病有关。然而，直接控制Zfp 521表达的调节因子尚未被表征。在这里，我们证明了转录因子SPI 1（PU.1）和HOXC 13协同调节Zfp 521的表达，并确定Zfp 521启动子的区域需要这种转录活性。我们还表明，SPI 1和HOXC 13以剂量依赖性方式激活Zfp 521。我们的数据支持这种体内调节机制的作用，因为在胎肝中过表达Hoxc 13的转基因小鼠显示Hoxc 13表达水平与Zfp 521表达之间存在强相关性。总之，这些实验提供了在非致癌背景下Zfp 521表达调控的见解。能够激活Zfp 521的转录因子的鉴定为进一步研究Zfp 521驱动的细胞分化过程和与Zfp 521错误表达相关的疾病中涉及的调控机制提供了基础。
The mouse zinc‐finger gene Zfp521 (also known as ecotropic viral insertion site 3; Evi3; and ZNF521 in humans) has been identified as a B‐cell proto‐oncogene, causing leukemia in mice following retroviral insertions in its promoter region that drive Zfp521 over‐expression. Furthermore, ZNF521 is expressed in human hematopoietic cells, and translocations between ZNF521 and PAX5 are associated with pediatric acute lymphoblastic leukemia. However, the regulatory factors that control Zfp521 expression directly have not been characterized. Here we demonstrate that the transcription factors SPI1 (PU.1) and HOXC13 synergistically regulate Zfp521 expression, and identify the regions of the Zfp521 promoter required for this transcriptional activity. We also show that SPI1 and HOXC13 activate Zfp521 in a dose‐dependent manner. Our data support a role for this regulatory mechanism in vivo, as transgenic mice over‐expressing Hoxc13 in the fetal liver show a strong correlation between Hoxc13 expression levels and Zfp521 expression. Overall these experiments provide insights into the regulation of Zfp521 expression in a nononcogenic context. The identification of transcription factors capable of activating Zfp521 provides a foundation for further investigation of the regulatory mechanisms involved in ZFP521‐driven cell differentiation processes and diseases linked to Zfp521 mis‐expression.
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