scribble mutants cooperate with oncogenic Ras or Notch to cause neoplastic overgrowth in Drosophila
scribble mutants cooperate with oncogenic Ras or Notch to cause neoplastic overgrowth in Drosophila
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DOI：
10.1093/emboj/cdg548
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发表时间：
2003-11-03
期刊：
影响因子：
11.4
通讯作者：
Richardson, HE
中科院分区：
文献类型：
--
作者：
Brumby, AM;Richardson, HE
癌症是一个多步骤的过程，涉及致癌或抑癌突变之间的合作以及肿瘤和周围正常组织之间的相互作用。在这里，我们提出了第一个描述的合作肿瘤发生在果蝇，通过使用一个系统，模仿哺乳动物的肿瘤的发展。我们已经使用的MARCM系统，以产生突变克隆的顶-基底细胞极性肿瘤抑制基因，涂鸦，在正常组织的背景下。我们发现，涂鸦突变体克隆在眼盘表现出异位表达的细胞周期蛋白E和异位细胞周期，但不过度生长，由于JNK通路介导的细胞死亡增加和周围的野生型组织。相反，当致癌Ras或Notch在scribble突变体克隆内表达时，细胞死亡被阻止并且肿瘤性肿瘤发展。这表明，在果蝇中，Ras和Notch的激活等位基因可以作为合作的癌基因在上皮肿瘤的发展，并强调了抑制癌基因和防止肿瘤形成的上皮极性调节剂的重要性。
Cancer is a multistep process involving cooperation between oncogenic or tumor suppressor mutations and interactions between the tumor and surrounding normal tissue. Here we present the first description of cooperative tumorigenesis in Drosophila, by using a system that mimics the development of tumors in mammals. We have used the MARCM system to generate mutant clones of the apical-basal cell polarity tumor suppressor gene, scribble, in the context of normal tissue. We show that scribble mutant clones in the eye disc exhibit ectopic expression of cyclin E and ectopic cell cycles, but do not overgrow due to increased cell death mediated by the JNK pathway and the surrounding wild-type tissue. In contrast, when oncogenic Ras or Notch is expressed within the scribble mutant clones, cell death is prevented and neoplastic tumors develop. This demonstrates, for the first time in Drosophila, that activated alleles of Ras and Notch can act as cooperating oncogenes in the development of epithelial tumors, and highlights the importance of epithelial polarity regulators in restraining oncogenes and preventing tumor formation.