An EBF3-mediated transcriptional program that induces cell cycle arrest and apoptosis
An EBF3-mediated transcriptional program that induces cell cycle arrest and apoptosis
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DOI：
10.1158/0008-5472.can-06-1713
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发表时间：
2006-10-01
期刊：
影响因子：
11.2
通讯作者：
Liao, Daiqing
中科院分区：
文献类型：
--
作者：
Zhao, Lisa Y.;Niu, Yuxin;Liao, Daiqing
在对可能的肿瘤抑制基因进行的全基因组筛查中，发现人类染色体10q26.3上的EBF3基因座在73%的脑肿瘤检查病例中缺失或甲基化。EBF3在正常脑中表达，但在脑瘤中沉默。因此，EBF3可能是一种肿瘤抑制因子。然而，EBF3基因失活是否也存在于其他类型的肿瘤中，以及EBF3在EBF3介导的肿瘤抑制中的作用尚不清楚。我们发现EBF3的表达导致了细胞周期停滞和细胞凋亡。P21(cip1/waf1)和p27(Kip1)和p57(Kip2)的持续激活对细胞周期蛋白依赖性激酶抑制物的表达产生了深远的影响，而与细胞存活和增殖有关的基因则受到抑制。在报告实验中，EBF3直接与p21(cip1/waf1)启动子结合并调控p21(cip1/waf1)和p27(Kip1)启动子的转录。EBF3表达并激活caspase-3后48h出现细胞凋亡。在脑、结直肠、乳腺、肝脏和骨肿瘤细胞系中观察到EBF3基因座的沉默，并在这些肿瘤细胞中的很大一部分细胞中用5-氮-2‘-脱氧胞苷和曲古抑素A处理后EBF3基因重新激活。因此，EBF3调控一个潜在的肿瘤抑制途径的转录程序。
In a genome-wide screen for putative tumor suppressor genes, the EBF3 locus on the human chromosome 10q26.3 was found to be deleted or methylated in 73% of the examined cases of brain tumors. EBF3 is expressed in normal brain but is silenced in brain tumors. Therefore, it is suggested that EBF3 is a tumor suppressor. However, it remains unknown whether inactivation of EBF3 locus also occurs in other types of tumors and what functions of EBF3 underlie EBF3-mediated tumor suppression. We show here that expression of EBF3 resulted in cell cycle arrest and apoptosis. The expression of cyclin-dependent kinase inhibitors was profoundly affected with early activation and then repression of p21(cip1/waf1) and persistent activation of both p27(kip1) and p57(kip2), whereas genes involved in cell survival and proliferation were suppressed. EBF3 bound directly to p21(cip1/waf1) promoter and regulated transcription from both p21(cip1/waf1) and p27(kip1) promoters in reporter assays. Apoptosis occurred 48 hours after EBF3 expression with caspase-3 activation. Silencing of the EBF3 locus was observed in brain, colorectal, breast, liver, and bone tumor cell lines and its reactivation was achieved on treatment with 5-aza-2'-deoxycytidine and trichostatin A in a significant portion of these tumor cells. Therefore, EBF3 regulates a transcriptional program underlying a putative tumor suppression pathway.