A Novel POK Family Transcription Factor, ZBTB5, Represses Transcription of p21CIP1 Gene
A Novel POK Family Transcription Factor, ZBTB5, Represses Transcription of p21CIP1 Gene
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DOI：
10.1074/jbc.m109.025817
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发表时间：
2009-07-24
影响因子：
4.8
通讯作者：
Hur, Man-Wook
中科院分区：
文献类型：
--
作者：
Koh, Dong-In;Choi, Won-Il;Hur, Man-Wook
通过染色质重塑和组蛋白去乙酰化的转录抑制被认为是肿瘤发生的驱动力。我们分离并鉴定了一种新的POZ域kruppel样锌指转录抑制因子ZBTB5 （zinc finger and BTB domain containing 5）。基因表达序列分析（SAGE）显示ZBTB5在视网膜母细胞瘤和肌肉癌组织中表达较高。免疫细胞化学显示ZBTB5定位于细胞核，特别是核斑。ZBTB5通过结合近端GC-box 5/6元件和两个远端p53响应元件（bp -2323类似于-2299；bp -1416类似于-1392）直接抑制细胞周期阻滞基因p21的转录。染色质免疫沉淀实验显示ZBTB5和p53在占据p53结合元件方面相互竞争。ZBTB5通过其POZ结构域与bcl -6相互作用的协同抑制因子-组蛋白去乙酰化酶复合物如BCoR（bcl -6相互作用的协同抑制因子）、NCoR（核受体协同抑制因子）和SMRT（类视黄醇和甲状腺受体的沉默介质）相互作用。这些相互作用导致Ac-H3和Ac-H4组蛋白在近端启动子上的去乙酰化，这在p21的转录抑制中很重要。MTT（3-（4,5-二甲基噻唑-2-基）-2,5-二苯基溴化四唑）试验和荧光活化细胞分选分析显示，ZBTB5刺激细胞增殖和细胞周期进展，显著增加s期细胞数量。总的来说，我们的数据表明ZBTB5是细胞周期阻滞基因p21的有效转录抑制因子，也是刺激细胞增殖的潜在原癌基因。
Transcriptional repression through chromatin remodeling and histone deacetylation has been postulated as a driving force for tumorigenesis. We isolated and characterized a novel POZ domain Kruppel-like zinc finger transcription repressor, ZBTB5 (zinc finger and BTB domain-containing 5). Serial analysis of gene expression (SAGE) analysis showed that ZBTB5 expression is higher in retinoblastoma and muscle cancer tissues. Immunocytochemistry showed that ZBTB5 was localized to the nucleus, particularly nuclear speckles. ZBTB5 directly repressed transcription of cell cycle arrest gene p21 by binding to the proximal GC-box 5/6 elements and the two distal p53-responsive elements (bp -2323 similar to -2299; bp -1416 similar to -1392). Chromatin immunoprecipitation assays showed that ZBTB5 and p53 competed with each other in occupying the p53 binding elements. ZBTB5 interacted with corepressor-histone deacetylase complexes such as BCoR(BCL-6-interacting corepressor), NCoR (nuclear receptor corepressor), and SMRT (silencing mediator for retinoid and thyroid receptors) via its POZ domain. These interactions resulted in deacetylation of histones Ac-H3 and Ac-H4 at the proximal promoter, which is important in the transcriptional repression of p21. MTT(3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assays and fluorescent-activated cell sorter analysis revealed that ZBTB5 stimulated both cell proliferation and cell cycle progression, significantly increasing the number of cells in S-phase. Overall, our data suggest that ZBTB5 is a potent transcription repressor of cell cycle arrest gene p21 and a potential proto-oncogene stimulating cell proliferation.