Multidrug resistance-associated protein MRP-1 regulates dauer diapause by its export activity in Caenorhabditis elegans
Multidrug resistance-associated protein MRP-1 regulates dauer diapause by its export activity in Caenorhabditis elegans
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DOI：
10.1242/dev.01909
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发表时间：
2005-07
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影响因子：
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通讯作者：
T. Yabe;N. Suzuki;T. Furukawa;T. Ishihara;I. Katsura
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文献类型：
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作者：
T. Yabe;N. Suzuki;T. Furukawa;T. Ishihara;I. Katsura
当多药耐药相关蛋白（MRPs）过表达时，通过细胞膜输出抗癌药物，从而赋予癌细胞耐药性，但它们在动物发育中的作用尚未阐明。在这里，我们展示了MRP同源物调节秀丽隐杆线虫的幼虫发育。秀丽隐杆线虫在不适合生长的条件下形成一种特殊的第三阶段幼虫，称为幼虫。相比之下，我们发现MRP -1 （MRP同源基因）的突变体即使在适合生长的条件下，在某些突变部分阻断胰岛素信号通路的背景下，也能形成大鼠幼虫。一个功能性的mrp-1::GFP基因在许多组织中表达，而野生型mrp-1基因必须在多个组织中表达才能形成野生型表型。人类MRP1可以替代秀丽隐杆线虫MRP-1进行幼虫调节，而人类MRP1转运活性的抑制剂破坏了这一功能，表明正常的幼虫调节需要出口活性。上位性研究表明，MRP-1既不参与TGF-β信号通路，也不参与cGMP信号通路。Mrp-1突变对胰岛素信号通路突变体的多组分表型的增强作用强于其他通路。因此，MRP-1通过其输出活性，支持胰岛素信号通路诱导正常（非死亡）生命周期。
Multidrug resistance-associated proteins (MRPs), when overexpressed, confer drug resistance to cancer cells by exporting anti-cancer agents through the cell membrane, but their role in animal development has not been elucidated. Here we show that an MRP homolog regulates larval development in the nematode Caenorhabditis elegans. C. elegans forms a special third-stage larva called a dauer larva under conditions inappropriate for growth. By contrast, we found that mutants in mrp-1, an MRP homolog gene, form dauer larvae even under conditions appropriate for growth, in the background of certain mutations that partially block the insulin signaling pathway. A functional mrp-1::GFP gene was shown to be expressed in many tissues, and the wild-type mrp-1 gene must be expressed in multiple tissues for a wild-type phenotype. Human MRP1 could substitute for C. elegans MRP-1 in dauer larva regulation, and an inhibitor of the human MRP1 transport activity impaired this function, showing that export activity is required for normal dauer larva regulation. Epistasis studies revealed that MRP-1 acts in neither the TGF-β nor the cGMP signaling pathway. mrp-1 mutations enhanced the dauer-constitutive phenotype of mutants in the insulin signaling pathway more strongly than that in other pathways. Thus, MRP-1, through its export activity, supports the induction of the normal (non-dauer) life cycle by the insulin signaling pathway.