Mutations of the HIPK2 gene in acute myeloid leukemia and myelodysplastic syndrome impair AML1-and p53-mediated transcription
Mutations of the HIPK2 gene in acute myeloid leukemia and myelodysplastic syndrome impair AML1-and p53-mediated transcription
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DOI：
10.1038/sj.onc.1210523
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发表时间：
2007-11-08
期刊：
影响因子：
8
通讯作者：
Kitabayashi, I.
中科院分区：
文献类型：
--
作者：
Li, X-L;Arai, Y.;Kitabayashi, I.
AML 1转录因子复合物是白血病相关染色体易位的最常见靶点。同源结构域相互作用蛋白激酶2（HIPK2）是AML1复合物的一部分，并激活AML1介导的转录。然而，HIPK2的染色体易位和突变尚未报道。在本研究中，我们筛选了50例急性髓细胞白血病（AML）和80例骨髓增生异常综合征（MDS）的HIPK2基因突变。结果表明，HIPK2的斑点滞留信号（SRS）结构域存在两个错义突变（R868W和N958I）。亚细胞定位分析表明，两个突变体主要定位于锥形或环形的核区域，并在一定程度上扩散于核内，而野生型主要定位于核斑点内。这些突变损害了AML1和HIPK2的重叠定位。突变体表现出降低活动和显性负功能的野生型蛋白在AML 1和p53依赖的转录。这些结果表明，HIPK2功能障碍可能在白血病的发病机制中发挥作用。
The AML1 transcription factor complex is the most frequent target of leukemia-associated chromosomal translocations. Homeodomain-interacting protein kinase 2 (HIPK2) is a part of the AML1 complex and activates AML1-mediated transcription. However, chromosomal translocations and mutations of HIPK2 have not been reported. In the current study, we screened mutations of the HIPK2 gene in 50 cases of acute myeloid leukemia (AML) and in 80 cases of myelodysplastic syndrome (MDS). Results indicated there were two missense mutations ( R868W and N958I) in the speckle-retention signal (SRS) domain of HIPK2. Subcellular localization analyses indicated that the two mutants were largely localized to nuclear regions with conical or ring shapes, and were somewhat diffused in the nucleus, in contrast to the wild type, which were mainly localized in nuclear speckles. The mutations impaired the overlapping localization of AML1 and HIPK2. The mutants showed decreased activities and a dominant-negative function over wild-type protein in AML1- and p53-dependent transcription. These findings suggest that dysfunction of HIPK2 may play a role in the pathogenesis of leukemia.