The DFNA5 gene, responsible for hearing loss and involved in cancer, encodes a novel apoptosis-inducing protein
The DFNA5 gene, responsible for hearing loss and involved in cancer, encodes a novel apoptosis-inducing protein
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DOI：
10.1038/ejhg.2011.63
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发表时间：
2011-09-01
影响因子：
5.2
通讯作者：
Van Laer, Lut
中科院分区：
文献类型：
--
作者：
de Beeck, Ken Op;Van Camp, Guy;Van Laer, Lut
DFNA 5基因是最早发现的一个常染色体显性遗传性听力损失（HL）的致病基因。已经发现了不同的突变，所有这些突变都发挥了高度特异性的功能获得效应，其中外显子8的跳跃导致HL。后来的报告揭示了该基因与不同类型的癌症有关。已经报道了DFNA 5在大比例的胃、结肠直肠和乳腺肿瘤中的表观遗传沉默以及p53依赖性转录活性，得出结论DFNA 5在不同常见类型的癌症中充当肿瘤抑制基因。尽管有这些数据，DFNA 5的分子功能尚未得到适当的研究。先前在酵母和哺乳动物细胞中用突变DFNA 5进行的转染研究显示突变蛋白的毒性作用，这在野生型蛋白转染后没有观察到。在这里，我们证明了DFNA 5是由两个域，分开的铰链区。当转染HEK 293 T细胞时，第一区域诱导凋亡，第二区域掩盖并可能调节这种凋亡诱导能力。此外，通过使用Dfna 5敲除小鼠的基因表达微阵列分析，证明了DFNA 5在生理环境中参与阿尔茨海默病相关途径。鉴于其在癌症发生中的重要作用，这一发现有望导致对凋亡在许多类型癌症中的作用的新见解。此外，它提供了一个新的证据支持细胞凋亡在单基因和复杂形式的HL的重要作用。European Journal of Human Genetics（2011）19，965-973; doi：10.1038/ejhg.2011.63; 2011年4月27日在线发表
DFNA5 was first identified as a gene causing autosomal dominant hearing loss (HL). Different mutations have been found, all exerting a highly specific gain-of-function effect, in which skipping of exon 8 causes the HL. Later reports revealed the involvement of the gene in different types of cancer. Epigenetic silencing of DFNA5 in a large percentage of gastric, colorectal and breast tumors and p53-dependent transcriptional activity have been reported, concluding that DFNA5 acts as a tumor suppressor gene in different frequent types of cancer. Despite these data, the molecular function of DFNA5 has not been investigated properly. Previous transfection studies with mutant DFNA5 in yeast and in mammalian cells showed a toxic effect of the mutant protein, which was not seen after transfection of the wild-type protein. Here, we demonstrate that DFNA5 is composed of two domains, separated by a hinge region. The first region induces apoptosis when transfected in HEK293T cells, the second region masks and probably regulates this apoptosis inducing capability. Moreover, the involvement of DFNA5 in apoptosis-related pathways in a physiological setting was demonstrated through gene expression microarray analysis using Dfna5 knockout mice. In view of its important role in carcinogenesis, this finding is expected to lead to new insights on the role of apoptosis in many types of cancer. In addition, it provides a new line of evidence supporting an important role for apoptosis in monogenic and complex forms of HL. European Journal of Human Genetics (2011) 19, 965-973; doi: 10.1038/ejhg.2011.63; published online 27 April 2011