Chibby, a nuclear β-catenin-associated antagonist of the Wnt/Wingless pathway
Chibby, a nuclear β-catenin-associated antagonist of the Wnt/Wingless pathway
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DOI：
10.1038/nature01570
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发表时间：
2003-04-24
期刊：
影响因子：
64.8
通讯作者：
Moon, RT
中科院分区：
文献类型：
--
作者：
Takemaru, KI;Yamaguchi, S;Moon, RT
癌蛋白β-连环蛋白不适当地激活下游靶基因与许多人类癌症的发生有关(1，2)。β-连环蛋白和果蝇对应的Armadillo通过与Tcf/Lef转录因子(3-6)结合，在典型的Wnt/Wingless途径中作为共激活因子发挥作用。在这里，我们报告了一种保守的核蛋白，命名为CHIBBY，它是在筛选直接与β-连环素的C-末端区域相互作用的蛋白质时发现的。在哺乳动物培养细胞中，我们证明了CHIBBY通过与Lef-1竞争结合β-catenin来抑制β-catenin介导的转录激活。通过RNA干扰抑制果蝇CHIBBY会导致模拟无翼功能获得表型的片段极性缺陷，以及无翼靶基因Engraded和Ultrabithorax的过度表达。此外，上位性实验表明，CHIBBY作用于无翼犰螂的下游和上游。
Inappropriate activation of downstream target genes by the oncoprotein beta-catenin is implicated in development of numerous human cancers(1,2). beta-catenin and its fruitfly counterpart Armadillo act as a coactivator in the canonical Wnt/Wingless pathway by binding to Tcf/Lef transcription factors(3-6). Here we report a conserved nuclear protein, named Chibby, which was identified in a screen for proteins that directly interact with the C-terminal region of beta-catenin. In mammalian cultured cells we demonstrate that Chibby inhibits beta-catenin-mediated transcriptional activation by competing with Lef-1 to bind to beta-catenin. Inhibition of Drosophila Chibby by RNA interference results in segment polarity defects that mimick a wingless gain-of-function phenotype, and overexpression of the wingless target genes engrailed and Ultrabithorax. In addition, epistasis experiments indicate that chibby acts downstream of wingless and upstream of armadillo.