Activating Met mutations produce unique tumor profiles in mice with selective duplication of the mutant allele
Activating Met mutations produce unique tumor profiles in mice with selective duplication of the mutant allele
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DOI：
10.1073/pnas.0407651101
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发表时间：
2004-12-07
影响因子：
11.1
通讯作者：
Woude, GV
中科院分区：
文献类型：
--
作者：
Graveel, C;Su, YL;Woude, GV
在遗传性乳头状肾癌和其他癌症中，已经观察到蛋氨酸酪氨酸激酶激活突变。这些突变已经在几个体外系统中进行了检测，在这些系统中，它们导致结构性Met激活、病灶形成和细胞运动，并在异种移植中产生肿瘤。为了研究这些突变对体内肿瘤发生的影响，我们在小鼠MET基因上产生了靶向突变的小鼠。建立了5个Met突变小鼠系：WT、D1226N、Y1228C、M1248T和M1248T/L1193V。我们观察到，携带D1226N、Y1228C和M1248T/11193V突变的小鼠发生肉瘤和一些淋巴瘤的频率很高，而M1248T小鼠发生癌症和淋巴瘤。值得注意的是，我们在大多数肿瘤中观察到了6号染色体的三体和突变的MET等位基因的重复，这与遗传性肾乳头状癌患者的报道类似。这些结果表明，激活Met突变和Met扩增在促进体内肿瘤发生中起关键作用。此外，我们的发现表明，Met激酶结构域中的不同突变可以影响发生的癌症类型。
Tyrosine kinase-activating mutations in Met have been observed in hereditary papillary renal carcinomas as well as in other cancers. These mutations have been examined in several in vitro systems, where they cause constitutive Met activation, focus formation, and cell motility, and are tumorigenic in xenografts. To study the influence of these mutations on tumorigenesis in vivo, we generated mice with targeted mutations in the murine met locus. The following five mouse lines with mutant Met were created: WT, D1226N, Y1228C, M1248T, and M1248T/L1193V. We observed that mice harboring D1226N, Y1228C, and M1248T/11193V mutations developed a high frequency of sarcomas and some lymphomas, whereas the M1248T mice developed carcinomas and lymphomas. Of considerable interest, we observed trisomy of chromosome 6 and duplication of the mutant met allele in a majority of the tumors, similar to what has been reported in patients with hereditary renal papillary carcinomas. These results demonstrate that activating Met mutations and met amplification play key roles in promoting tumorigenesis in vivo. Moreover, our findings show that different mutations in the Met kinase domain can influence the types of cancers that develop.