Read Renee D, Goodfellow Paul J, Mardis Elaine R, Novak Nancy, Armstrong Jon R, Cagan Ross L
Department of Genetics, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Genetics. 2005 Nov;171(3):1057-81. doi: 10.1534/genetics.104.038018. Epub 2005 Jun 18.
Dominant mutations in the Ret receptor tyrosine kinase lead to the familial cancer syndrome multiple endocrine neoplasia type 2 (MEN2). Mammalian tissue culture studies suggest that RetMEN2 mutations significantly alter Ret-signaling properties, but the precise mechanisms by which RetMEN2 promotes tumorigenesis remain poorly understood. To determine the signal transduction pathways required for RetMEN2 activity, we analyzed analogous mutations in the Drosophila Ret ortholog dRet. Overexpressed dRetMEN2 isoforms targeted to the developing retina led to aberrant cell proliferation, inappropriate cell fate specification, and excessive Ras pathway activation. Genetic analysis indicated that dRetMEN2 acts through the Ras-ERK, Src, and Jun kinase pathways. A genetic screen for mutations that dominantly suppress or enhance dRetMEN2 phenotypes identified new genes that are required for the phenotypic outcomes of dRetMEN2 activity. Finally, we identified human orthologs for many of these genes and examined their status in human tumors. Two of these loci showed loss of heterozygosity (LOH) within both sporadic and MEN2-associated pheochromocytomas, suggesting that they may contribute to Ret-dependent oncogenesis.
Ret 受体酪氨酸激酶中的显性突变会导致家族性癌症综合征 2 型多发性内分泌肿瘤（MEN2）。哺乳动物组织培养研究表明，RetMEN2 突变会显著改变 Ret 信号特性，但 RetMEN2 促进肿瘤发生的确切机制仍知之甚少。为了确定 RetMEN2 活性所需的信号转导途径，我们分析了果蝇 Ret 直系同源基因 dRet 中的类似突变。靶向发育中的视网膜过表达的 dRetMEN2 异构体导致异常细胞增殖、不适当的细胞命运特化以及 Ras 途径过度激活。遗传分析表明，dRetMEN2 通过 Ras-ERK、Src 和 Jun 激酶途径发挥作用。对显性抑制或增强 dRetMEN2 表型的突变进行的遗传筛选鉴定出了 dRetMEN2 活性表型结果所需的新基因。最后，我们鉴定了其中许多基因的人类直系同源基因，并检查了它们在人类肿瘤中的状态。其中两个位点在散发性和 MEN2 相关的嗜铬细胞瘤中均显示杂合性缺失（LOH），这表明它们可能有助于 Ret 依赖性肿瘤发生。
