A constitutively active epidermal growth factor receptor cooperates with disruption of G1 cell-cycle arrest pathways to induce glioma-like lesions in mice
A constitutively active epidermal growth factor receptor cooperates with disruption of G1 cell-cycle arrest pathways to induce glioma-like lesions in mice
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DOI：
10.1101/gad.12.23.3675
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发表时间：
1998-12-01
影响因子：
10.5
通讯作者：
Varmus, HE
中科院分区：
文献类型：
--
作者：
Holland, EC;Hively, WP;Varmus, HE
表皮生长因子受体(EGFR)基因在30%-50%的人多形性胶质母细胞瘤(GBM)中扩增或突变。这些突变通常与INK4a-ARF基因座的缺失有关，INK4a-ARF基因座编码两种基因产物(p16(INK4a)和p19(ARF))，涉及细胞周期停滞和细胞凋亡。我们研究了EGFR突变在胶质瘤发生中的作用，利用禽类逆转录病毒载体将突变的Eger基因转移到表达逆转录病毒受体基因TV-a的转基因小鼠的胶质前体细胞和星形胶质细胞中。TVA，在脑细胞类型特异性启动子的控制下。我们证明，在神经胶质细胞系的细胞中表达具有结构性活性的突变形式的Eger可以引起与人类胶质瘤许多相似的病变。与星形胶质细胞特异的胶质纤维酸性蛋白(GFAP)启动子的表达TV-a的小鼠相比，将基因转移到表达TV-a的祖细胞特异性Nestin启动子的小鼠中更容易发生这些损害，这表明肿瘤从胶质细胞谱系中的未成熟细胞更有效地产生。此外，EGFR诱导的胶质瘤形成似乎需要编码与细胞周期停滞通路有关的蛋白质的基因发生额外的突变。我们通过同时感染携带CDK4和EGFR载体的转基因小鼠TV或感染带有中断INK4a-ARF基因座的转基因小鼠仅携带EGFR载体来产生这些组合。此外，除非小鼠也感染了携带CDK4的载体，否则EGFR诱导的胶质瘤不会与P53缺失一起发生。小鼠所需的基因损伤的神经胶质瘤组合与人类胶质瘤中发现的相似。
The epidermal growth factor receptor (EGFR) gene is amplified or mutated in 30%-50% of human gliobastoma multiforme (GBM). These mutations are associated usually with deletions of the INK4a-ARF locus, which encodes two gene products (p16(INK4a) and p19(ARF)) involved in cell-cycle arrest and apoptosis. We have investigated the role of EGFR mutation in gliomagenesis, using avian retroviral vectors to transfer a mutant EGER gene to glial precursors and astrocytes in transgenic mice expressing tv-a, a gene encoding the retrovirus receptor. TVA, under control of brain cell type-specific promoters. We demonstrate that expression of a constitutively active, mutant form of EGER in cells in the glial lineage can induce lesions with many similarities to human gliomas. These lesions occur more frequently with gene transfer to mice expressing tv-a from the progenitor-specific nestin promoter than to mice expressing tv-a from the astrocyte-specific glial fibrillary acidic protein (GFAP) promoter, suggesting that tumors arise more efficiently from immature cells in the glial lineage. Furthermore, EGFR-induced gliomagenesis appears to require additional mutations in genes encoding proteins involved in cell-cycle arrest pathways. We have produced these combinations by simultaneously infecting tv-a transgenic mice with vectors carrying cdk4 and EGFR or by infecting tv-a transgenic mice bearing a disrupted INK4a-ARF locus with the EGFR-carrying vector alone. Moreover, EGFR-induced gliomagenesis does not occur in conjunction with p53 deficiency, unless the mice are also infected with a vector carrying cdk4. The gliomagenic combinations of genetic lesions required in mice are similar to those found in human gliomas.