WWOX, a novel WW domain-containing protein mapping to human chromosome 16q23.3-24.1, a region frequently affected in breast cancer.
WWOX, a novel WW domain-containing protein mapping to human chromosome 16q23.3-24.1, a region frequently affected in breast cancer.
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发表时间：
2000-04
期刊：
影响因子：
11.2
通讯作者：
A. Bednarek;K. J. Laflin;R. Daniel;Q. Liao;K. A. Hawkins;Claudio Marcelo Aldaz
中科院分区：
文献类型：
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作者：
A. Bednarek;K. J. Laflin;R. Daniel;Q. Liao;K. A. Hawkins;Claudio Marcelo Aldaz
进行研究的最终目标是鉴定定位到染色体区域16q23.3-24.1的感兴趣基因，该区域通常受乳腺癌中等位基因丢失的影响。为此，我们生成了跨越序列标记位点标记D16 S518和D16 S516之间的基因组区域的详细物理图谱。为了确定候选基因，我们使用鸟枪基因组测序以及分离和分析转录本映射到感兴趣的区域。我们鉴定并克隆了一个新的基因，其基因组结构跨越了整个感兴趣的区域。我们将该基因命名为WWOX，因为它包含两个WW结构域，该结构域与短链脱氢酶/还原酶家族具有高度同源性的区域偶联。WWOX的开放阅读框长1245 bp，编码414个氨基酸。该基因由9个外显子组成。我们在一组乳腺癌细胞系中进行了WWOX外显子的突变筛查，其中大多数是所示16 q基因组区域的半合子。我们没有发现突变的证据，因此表明WWOX可能不是肿瘤抑制基因。然而，我们观察到，一个纯合缺失的情况下，以及两个先前描述的易位断点映射到该基因的内含子区域。我们推测，WWOX可能跨越尚未确定的共同脆性位点FRA 16 D区域。在表达研究中，我们发现与正常乳腺细胞和组织相比，WWOX在乳腺癌细胞系中过表达。WWOX的最高正常表达在睾丸、卵巢和前列腺等经尿道调节的组织中观察到。这种表达模式和短链脱氢酶/还原酶结构域和特定氨基酸特征的存在表明WWOX在类固醇代谢中的作用。有趣的是，WWOX结构中WW结构域的存在表明该蛋白质与其他蛋白质物理相互作用的可能性。WWOX的独特特征及其与癌症过程的可能关联使其成为进一步研究的有趣目标。
Studies were conducted with the final goal of identifying genes of interest mapping to the chromosome region 16q23.3-24.1, an area commonly affected by allelic losses in breast cancer. To this end we generated a detailed physical map of the genomic region spanning between sequence-tagged site markers D16S518 and D16S516. To identify candidate genes, we used shotgun genomic sequencing as well as isolation and analysis of transcripts mapping to the area of interest. We identified and cloned a novel gene, the genomic structure of which spans the whole region of interest. We named this gene WWOX because it contains two WW domains coupled to a region with high homology to the short-chain dehydrogenase/reductase family of enzymes. The ORF of WWOX is 1245 bp long, encoding a 414-amino acid protein. This gene is composed of nine exons. We performed a mutation screening of WWOX exons in a panel of breast cancer lines, most of which are hemizygous for the 16q genomic region indicated. We found no evidence of mutations, thus indicating that WWOX is probably not a tumor suppressor gene. However, we observed that one case of homozygous deletion as well as two previously described translocation breakpoints map to intronic regions of this gene. We speculate that WWOX may span the yet uncharacterized common fragile site FRA16D region. In expression studies we found overexpression of WWOX in breast cancer cell lines when compared with normal breast cells and tissues. The highest normal expression of WWOX was observed in hormonally regulated tissues such as testis, ovary, and prostate. This expression pattern and the presence of a short-chain dehydrogenase/reductase domain and specific amino acid features suggest a role for WWOX in steroid metabolism. Interestingly, the presence of WW domains in the structure of WWOX indicate the likelihood that this protein physically interacts with other proteins. The unique features of WWOX and its possible association with cancer processes make it an interesting target for further investigation.