Emerging roles of the EBF family of transcription factors in tumor suppression.
Emerging roles of the EBF family of transcription factors in tumor suppression.
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DOI：
10.1158/1541-7786.mcr-09-0229
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发表时间：
2009-12
期刊：
影响因子：
--
通讯作者：
Liao D
中科院分区：
文献类型：
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作者：
Liao D
各种发育途径的改变是癌症的常见主题。早期B细胞因子（early B-cell factors，EBF）是一类具有非典型锌指和螺旋-环-螺旋结构的高度保守的DNA结合转录因子。它们参与几种细胞谱系的分化和成熟，包括B祖淋巴母细胞、神经元前体细胞和成骨细胞祖细胞。在B细胞发育过程中，EBF 1是Pax 5表达所必需的，Pax 5是产生抗体分泌细胞的必需因子。越来越多的证据表明，EBF 1基因的基因组缺失与B祖细胞急性淋巴细胞白血病（ALL）的发病、耐药和复发有关。在胶质母细胞瘤（GBM）中，染色体10 q中EBF 3基因座的表观遗传沉默和基因组缺失非常常见。引人注目的是，GBM中EBF 3丢失的频率与Pten丢失的频率相似，Pten是胶质瘤发生的关键抑制因子。在GBM中的EBF 3和胰腺导管腺癌中的EBF 1和EBF 3中检测到癌症特异性体细胞突变。这些错义突变发生在DNA结合结构域或保守的IPT/TIG结构域，表明它们可能破坏这两种蛋白的功能。功能研究显示，EBF 3抑制细胞增殖所需基因的表达（例如，细胞周期蛋白和CDK）和存活（例如，Mcl-1和Daxx），但激活参与细胞周期停滞的那些（例如，p21和p27），导致生长抑制和凋亡。因此，EBF代表了新的肿瘤抑制因子，其失活阻断了正常发育并有助于多种类型的人类癌症的肿瘤发生。
Alterations in various developmental pathways are common themes in cancer. The early B-cell factors (EBFs) are a family of four highly conserved DNA-binding transcription factors with an atypical zinc finger and helix-loop-helix motif. They are involved in the differentiation and maturation of several cell lineages including B-progenitor lymphoblasts, neuronal precursors, and osteoblast progenitors. During B-cell development, EBF1 is required for the expression of Pax5, an essential factor for the production of antibody-secreting cells. Accumulating evidence indicates that genomic deletion of the EBF1 gene contributes to the pathogenesis, drug resistance and relapse of B-progenitor acute lymphoblastic leukemia (ALL). Epigenetic silencing and genomic deletion of the EBF3 locus in chromosome 10q are very frequent in glioblastoma (GBM). Strikingly, the frequency of EBF3 loss in GBM is similar to that of the loss of Pten, a key suppressor of gliomagenesis. Cancer-specific somatic mutations were detected in EBF3 in GBM and in both EBF1 and EBF3 in pancreatic ductal adenocarcinoma. These missense mutations occur in the DNA-binding domain or the conserved IPT/TIG domain, suggesting that they might disrupt the functions of these two proteins. Functional studies revealed that EBF3 represses the expression of genes required for cell proliferation (e.g., cyclins and CDKs) and survival (e.g., Mcl-1 and Daxx) but activates those involved in cell cycle arrest (e.g., p21 and p27), leading to growth suppression and apoptosis. Therefore, EBFs represent new tumor suppressors whose inactivation blocks normal development and contributes to tumorigenesis of diverse types of human cancer.