Mammalian homologs of seven in absentia regulate DCC via the ubiquitin-proteasome pathway
Mammalian homologs of seven in absentia regulate DCC via the ubiquitin-proteasome pathway
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DOI：
10.1101/gad.11.20.2701
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发表时间：
1997-10-15
影响因子：
10.5
通讯作者：
Fearon, ER
中科院分区：
文献类型：
--
作者：
Hu, G;Zhang, S;Fearon, ER
DCC（在结直肠癌中缺失）被假定作为轴突和细胞导向因子netrin-1的跨膜受体发挥作用。我们在这里报告，DCC胞质结构域结合蛋白质编码的哺乳动物同源的果蝇七缺席（新浪）基因，以及果蝇新浪。Sina在R7光感受器发育中具有关键作用，并且显示出与其哺乳动物同源物（称为Siah）的85%以上的氨基酸同一性，但是Sina/Siah蛋白的功能尚未被确定。因此，我们试图进一步描述他们与DCC的互动。免疫荧光研究表明，Sina/Siah蛋白主要定位于细胞质中，并与DCC相关。DCC被发现是泛素化的，并且Sina/Siah蛋白调节其表达。蛋白酶体抑制剂阻断了Sina/Siah对DCC的作用，并且Sina/Siah蛋白与泛素缀合酶（Ubcs）相互作用。突变体Siah蛋白缺乏氨基末端Ubc结合序列与DCC复合，但没有降解it. The在体内之间的相互作用Sina/Siah和DCC证实通过研究转基因果蝇品系，其中DCC和Sina异位表达在眼睛。综上所述，这些数据意味着Sina/Siah蛋白通过泛素-蛋白酶体途径调节DCC和其他蛋白。
DCC (deleted in colorectal cancer) is postulated to function as transmembrane receptor for the axon and cell guidance factor netrin-1. We report here that the DCC cytoplasmic domain binds to proteins encoded by mammalian homologs of the Drosophila seven in absentia (sina) gene, as well as Drosophila Sina. Sina has a critical role in R7 photoreceptor development and shows upward of 85% amino acid identity with its mammalian homologs (termed Siahs), but the function of the Sina/Siah proteins has not been defined. We sought, therefore, to characterize further their interaction with DCC. Immunofluorescence studies suggested the Sina/Siah proteins localized predominantly in the cytoplasm and in association with DCC. DCC was found to be ubiquitinated and the Sina/Siah proteins regulated its expression. Proteasome inhibitors blocked the effects of Sina/Siah on DCC, and the Sina/Siah proteins interacted with ubiquitin-conjugating enzymes (Ubcs). A mutant Siah protein lacking the amino-terminal Ubc-binding sequences complexed with DCC, but did not degrade it. The in vivo interaction between Sina/Siah and DCC was confirmed through studies of transgenic Drosophila lines in which DCC and Sina were ectopically expressed in the eye. Taken together, the data imply that the Sina/Siah proteins regulate DCC and perhaps other proteins via the ubiquitin-proteasome pathway.