Cloning and characterization of a novel human histone deacetylase, HDAC8
Cloning and characterization of a novel human histone deacetylase, HDAC8
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DOI：
10.1042/0264-6021:3500199
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发表时间：
2000-08-15
影响因子：
4.1
通讯作者：
Clark, JM
中科院分区：
文献类型：
--
作者：
Buggy, JJ;Sideris, ML;Clark, JM
组蛋白去乙酰化酶（HDAC）是通过影响细胞核中核心组蛋白的乙酰化状态而参与转录调控的酶的不断增长的家族。已知HDAC在细胞增殖的调节中具有关键作用[Bibrim，Miska，McCance，Reid，班尼斯特和Kouzarides（1998）Nature（伦敦）391，597-600]，并且HDAC复合物的异常募集已被证明是急性早幼粒细胞白血病中细胞转化机制的关键步骤[Grignani，De Matteis，Nervi，Tomassoni，Gelmetti，Cioce，Fanelli，Ruthardt，费拉拉，Zamir等人（1998）Nature（伦敦）391，815-818; Lin，Nagy，Inoue，Shao，米勒和Evans（1998），Nature（伦敦）391，811-814]。在这里，我们提出了完整的核苷酸序列的cDNA克隆，称为HDAC 8，编码的蛋白质产物与相似的RPD 3类（I）的HDAC。预测的377个残基的HDAC 8产品包含一个较短的C-末端延伸相对于其类别的其他成员。在两种细胞系统中表达后，免疫纯化的HDAC 8显示出对组蛋白H4肽底物以及对核心组蛋白具有可抑制他汀A和丁酸钠的HDAC活性。表达谱揭示了HDAC在每个测试组织中以及在几种肿瘤系中的不同程度的表达。预测活性位点内两个相邻组氨酸残基的突变严重降低活性，证实这些残基对于HDAC 8酶活性是重要的。最后，辐射杂交作图后的连锁分析将HDAC 8定位于染色体位置Xq21.2-Xq21.3。这些结果证实HDAC 8是HDAC家族的新成员。
Histone deacetylases (HDACs) are a growing family of enzymes implicated in transcriptional regulation by affecting the acetylation state of core histones in the nucleus of cells. HDACs are known to have key roles in the regulation of cell proliferation [Brehm, Miska, McCance, Reid, Bannister and Kouzarides (1998) Nature (London) 391, 597-600], and aberrant recruitment of an HDAC complex has been shown to be a key step in the mechanism of cell transformation in acute promyelocytic leukaemia [Grignani, De Matteis, Nervi, Tomassoni, Gelmetti, Cioce, Fanelli, Ruthardt, Ferrara, Zamir et al. (1998) Nature (London) 391, 815-818; Lin, Nagy, Inoue, Shao, Miller and Evans (1998), Nature (London) 391, 811-814]. Here we present the complete nucleotide sequence of a cDNA clone, termed HDAC8, that encodes a protein product with similarity to the RPD3 class (I) of HDACs. The predicted 377-residue HDAC8 product contains a shorter C-terminal extension relative to other members of its class. After expression in two cell systems, immunopurified HDAC8 is shown to possess trichostatin A- and sodium butyrate-inhititable HDAC activity on histone H4 peptide substrates as well as on core histones. Expression profiling reveals the expression of HDACs to various degrees in every tissue tested and also in several tumour lines. Mutation of two adjacent histidine residues within the predicted active site severely decreases activity, confirming these residues as important for HDAC8 enzyme activity. Finally, linkage analysis after radiation hybrid mapping has localized HDAC8 to chromosomal position Xq21.2-Xq21.3. These results confirm HDAC8 as a new member of the HDAC family.