Identification of candidate cancer-causing genes in mouse brain tumors by retroviral tagging
Identification of candidate cancer-causing genes in mouse brain tumors by retroviral tagging
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DOI：
10.1073/pnas.0402716101
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发表时间：
2004-08-03
影响因子：
11.1
通讯作者：
Westermark, B
中科院分区：
文献类型：
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作者：
Johansson, FK;Brodd, J;Westermark, B
小鼠逆转录病毒可通过插入诱变宿主基因引起小鼠恶性肿瘤。然而，使用逆转录病毒标记作为识别致癌基因的一种手段，几乎完全局限于造血肿瘤。这项研究的目的是开发一个系统，允许在恶性脑肿瘤候选基因的逆转录病毒标记。用编码血小板衍生生长因子（PDGF） b链的重组Moloney小鼠白血病病毒诱导小鼠胶质瘤。潜在的想法是，肿瘤通过PDGF介导的自分泌生长刺激和PDGF在胶质瘤形成过程中协同基因的插入突变的结合而进化。通过克隆和测序逆转录病毒侧翼片段，确定了常见的插入位点（在多个肿瘤中标记的位点），然后对小鼠基因组数据库进行BLAST搜索。发现了许多候选脑肿瘤位点（BtIs）。其中一些bti与已知的致瘤基因相对应；这些发现有力地支持了我们实验方法的基本观点。其他BUS基因在转化或肿瘤发生中具有迄今未被证实的作用。我们的研究结果表明，用生长因子编码病毒标记逆转录病毒可能是鉴定非造血肿瘤候选致瘤基因的有力手段。
Murine retroviruses may cause malignant tumors in mice by insertional mutagenesis of host genes. The use of retroviral tagging as a means of identifying cancer-causing genes has, however, almost entirely been restricted to hematopoietic tumors. The aim of this study was to develop a system allowing for the retroviral tagging of candidate genes in malignant brain tumors. Mouse gliomas were induced by a recombinant Moloney murine leukemia virus encoding platelet-derived growth factor (PDGF) B-chain. The underlying idea was that tumors evolve through a combination of PDGF-mediated autocrine growth stimulation and insertional mutagenesis of genes that cooperate with PDGF in gliomagenesis. Common insertion sites (loci that were tagged in more than one tumor) were identified by cloning and sequencing retroviral flanking segments, followed by BLAST searches of mouse genome databases. A number of candidate brain tumor loci (BtIs) were identified. Several of these BtIs correspond to known tumor-causing genes; these findings strongly support the underlying idea of our experimental approach. Other BUS harbor genes with a hitherto unproven role in transformation or oncogenesis. Our findings indicate that retroviral tagging with a growth factor-encoding virus may be a powerful means of identifying candidate tumor-causing genes in nonhematopoietic tumors.