Ahi-1, a novel gene encoding a modular protein with WD40-repeat and SH3 domains, is targeted by the Ahi-1 and Mis-2 provirus integrations
Ahi-1, a novel gene encoding a modular protein with WD40-repeat and SH3 domains, is targeted by the Ahi-1 and Mis-2 provirus integrations
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DOI：
10.1128/jvi.76.18.9046-9059.2002
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发表时间：
2002-09-01
影响因子：
5.4
通讯作者：
Jolicoeur, P
中科院分区：
文献类型：
--
作者：
Jiang, XY;Hanna, Z;Jolicoeur, P
Ahi-1 位点最初被鉴定为 Abelson 前 B 细胞淋巴瘤中常见的辅助原病毒整合位点，并显示与 c-myb 原癌基因密切相关。由于在 Abelson 鼠白血病病毒诱导的前 B 淋巴瘤中没有发现 c-myb 表达的显着改变，该淋巴瘤含有插入 Ahi-1 位点的原病毒，这表明它含有另一个基因，其失调与肿瘤形成有关。在这里，我们报告了这些原病毒插入突变靶向的新基因（Ahi-1）的鉴定及其 cDNA 的克隆。 Ahi-1 原病毒插入位于该基因的 3' 端，呈逆转录方向，其中大多数位于最后一个外显子周围和下游，而另一个插入位于 22 号内含子内。此外，还发现另一个先前识别的原病毒插入位点 Mis-2 位于 Ahi-1 基因的第 16 个内含子内。 Ahi-1 cDNA 编码 1,047 个氨基酸的蛋白质。预测的 Ahi-1 蛋白是一种模块化蛋白，包含一个 SH3 基序和 7 个 WD40 重复序列。 Ahi-1 基因在哺乳动物中保守，编码 5 和 4.2 kb 的两种主要 RNA 种类以及其他几种较短的剪接变体。 Ahi-1 基因在小鼠胚胎以及小鼠和大鼠的多个器官中表达，特别是在大脑和睾丸中表达量较高。在含有 Ahi-1 插入突变的肿瘤细胞中，鉴定出截短的 Ahi-1/病毒融合转录本，包括一些删除了 SH3 结构域的剪接变体。因此，Ahi-1 是原病毒插入的新基因，其编码的蛋白质具有信号分子的多种特征。因此，Ahi-1可能在正常细胞的信号转导中发挥重要作用，并可能参与肿瘤的发展，可能与其他癌基因（例如v-abl和c-myc）或肿瘤抑制基因（Nfl）合作，因为Ahi-1插入位点在含有v-abl缺陷逆转录病毒或c-myc转基因的肿瘤或表现出Nfl缺失的肿瘤中被鉴定。
The Ahi-1 locus was initially identified as a common helper provirus integration site in Abelson pre-B-cell lymphomas and shown to be closely linked to the c-myb proto-oncogene. Since no significant alteration of c-myb expression was found in Abelson murine leukemia virus-induced pre-B-lymphomas harboring a provirus inserted within the Ahi-1 locus, this suggested that it harbors another gene whose dysregulation is involved in tumor formation. Here we report the identification of a novel gene (Ahi-1) targeted by these provirus insertional mutations and the cloning of its cDNA. The Ahi-1 proviral insertions were found at the 3' end of the gene, in an inverse transcriptional orientation, with most of them located around and downstream of the last exon, whereas another insertion was within intron 22. In addition, another previously identified provirus insertion site, Mis-2, was found to map within the 16th intron of the Ahi-1 gene. The Ahi-1 cDNA encodes a 1,047-amino-acid protein. The predicted Ahi-1 protein is a modular protein that contains one SH3 motif and seven WD40 repeats. The Ahi-1 gene is conserved in mammals and encodes two major RNA species of 5 and 4.2 kb and several other shorter splicing variants. The Ahi-1 gene is expressed in mouse embryos and in several organs of the mouse and rat, notably at high levels in the brain and testes. In tumor cells harboring insertional mutations in Ahi-1, truncated Ahi-1/viral fused transcripts were identified, including some splicing variants with deletion of the SH3 domain. Therefore, Ahi-1 is a novel gene targeted by provirus insertion and encoding a protein that exhibits several features of a signaling molecule. Thus, Ahi-1 may play an important role in signal transduction in normal cells and may be involved in tumor development, possibly in cooperation with other oncogenes (such as v-abl and c-myc) or with a tumor suppressor gene (Nfl), since Ahi-1 insertion sites were identified in tumors harboring v-abl defective retroviruses or a c-myc transgene or in tumors exhibiting deletion of Nfl.