The human protein Hugl-1 substitutes for Drosophila Lethal giant larvae tumour suppressor function in vivo
The human protein Hugl-1 substitutes for Drosophila Lethal giant larvae tumour suppressor function in vivo
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DOI：
10.1038/sj.onc.1208023
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发表时间：
2004-11-11
期刊：
影响因子：
8
通讯作者：
Strand, D
中科院分区：
文献类型：
--
作者：
Grifoni, D;Garoia, F;Strand, D
果蝇致死性巨幼虫基因（lgl）、大圆盘基因（dlg）和scribble基因（scribb）是共同的肿瘤抑制基因，它们的功能丧失导致细胞极性和组织结构的破坏、不受控制的增殖和肿瘤病变的生长。这些基因的哺乳动物同源物是高度保守的，并且关于它们在人类细胞增殖控制和肿瘤发生中的作用的证据正在出现。在这里，我们调查果蝇致死的巨大幼虫和人类同源Hugl-1（Llgl 1）之间的功能保守性。我们首先表明Hugl-1在人类实体恶性肿瘤中丢失，支持其作为人类肿瘤抑制因子的作用。Hugl-1在纯合Igl果蝇突变体中的表达能够挽救幼虫致死率;成虫组织不显示任何肿瘤特征，Dig和Scrib显示出正确的定位;动物经历完全变态并孵化为可存活的成虫。这些数据表明Hugl-1可以作为果蝇中的肿瘤抑制因子，因此是lgl的功能同源物。此外，我们的数据表明，包括肿瘤抑制因子lgl，dlg和scrib的遗传途径可能在哺乳动物中是保守的，因为人类scrib和哺乳动物dlg也可以拯救它们各自的果蝇突变。我们的研究结果突出了果蝇作为模型系统的有用性，用于在体内研究人类癌症中细胞极性丧失和细胞增殖控制的机制。
Drosophila lethal giant larvae (lgl), discs large (dlg) and scribble (scrib) are tumour suppressor genes acting in a common pathway, whose loss of function leads to disruption of cell polarity and tissue architecture, uncontrolled proliferation and growth of neoplastic lesions. Mammalian homologues of these genes are highly conserved and evidence is emerging concerning their role in cell proliferation control and tumorigenesis in humans. Here we investigate the functional conservation between Drosophila lethal giant larvae and its human homologue Hugl-1(Llgl1). We first show that Hugl-1 is lost in human solid malignancies, supporting its role as a tumour suppressor in humans. Hugl-1 expression in homozygous Igl Drosophila mutants is able to rescue larval lethality; imaginal tissues do not show any neoplastic features, with Dig and Scrib exhibiting the correct localization; animals undergo a complete metamorphosis and hatch as viable adults. These data demonstrate that Hugl-1 can act as a tumour suppressor in Drosophila and thus is the functional homologue of lgl. Furthermore, our data suggest that the genetic pathway including the tumour suppressors lgl, dlg and scrib may be conserved in mammals, since human scrib and mammalian dlg can also rescue their respective Drosophila mutations. Our results highlight the usefulness of fruit fly as a model system for investigating in vivo the mechanisms linking loss of cell polarity and cell proliferation control in human cancers.