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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Enhanced secretion of glycocholic acid in a specially adapted cell line is associated with overexpression of apparently novel ATP-binding cassette proteins.
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Enhanced secretion of glycocholic acid in a specially adapted cell line is associated with overexpression of apparently novel ATP-binding cassette proteins.

机译：在特别适应的细胞系中，糖胆酸分泌的增加与表面上新颖的ATP结合盒蛋白的过表达有关。

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摘要

Secretion of anionic endo- and xenobiotics is essential for the survival of animal and plant cells; however, the underlying molecular mechanisms remain uncertain. To better understand one such model system--i.e., secretion of bile acids by the liver--we utilized a strategy analogous to that employed to identify the multidrug resistance (mdr) genes. We synthesized the methyl ester of glycocholic acid (GCE), which readily enters cells, where it is hydrolyzed to yield glycocholic acid, a naturally occurring bile acid. The rat hepatoma-derived HTC cell line gradually acquired resistance to GCE concentrations 20-fold higher than those which inhibited growth of naive cells, yet intracellular accumulation of radiolabel in resistant cells exposed to [14C]GCE averaged approximately 25% of that in nonresistant cells. As compared with nonresistant cells, resistant cells also exhibited (i) cross-resistance to colchicine, a known mdr substrate, but not to other noxious substances transported by hepatocytes; (ii) increased abundance on Northern blot of mRNA species up to 7-10 kb recognized by a probe for highly conserved nucleotide-binding domain (NBD) sequences of ATP-binding cassette (ABC) proteins; (iii) increased abundance, as measured by RNase protection assay, of mRNA fragments homologous to a NBD cRNA probe; and (iv) dramatic overexpression, as measured by Western blotting and immunofluorescence, of a group of 150- to 200-kDa plasma membrane proteins recognized by a monoclonal antibody against a region flanking the highly conserved NBD of mdr/P-glycoproteins. Finally, Xenopus laevis oocytes injected with mRNA from resistant cells and incubated with [14C]GCE secreted radiolabel more rapidly than did control oocytes. Enhanced secretion of glycocholic acid in this cell line is associated with overexpression of ABC/mdr-related proteins, some of which are apparently novel and are likely to include a bile acid transport protein.
机译：阴离子内源性和异源性生物的分泌对于动植物细胞的生存至关重要。然而，潜在的分子机制仍然不确定。为了更好地了解这样一种模型系统-即肝脏分泌胆汁酸-我们采用了类似于识别多药耐药性（mdr）基因的策略。我们合成了糖胆酸的甲酯（GCE），该甲酯容易进入细胞，在水解后产生天然存在的胆汁酸糖胆酸。大鼠肝癌衍生的HTC细胞系对GCE浓度的耐受性逐渐比对抑制幼稚细胞生长的GCE浓度高20倍，但暴露于[14C] GCE的耐药细胞中放射性标记的细胞内积累平均约为非耐药细胞中的25％ 。与非抗性细胞相比，抗性细胞还表现出（i）对秋水仙碱（一种已知的mdr底物）的交叉抗性，但对肝细胞转运的其他有害物质则无交叉抗性； （ii）被探针识别的ATP结合盒（ABC）蛋白的高度保守的核苷酸结合域（NBD）序列的探针识别的mRNA物种的Northern blot丰度提高至7-10 kb； （iii）通过核糖核酸酶保护试验测定，与NBD cRNA探针同源的mRNA片段的丰度增加； （iv）通过蛋白质印迹和免疫荧光测定，由单克隆抗体识别的针对mdr / P-糖蛋白高度保守的NBD侧翼区域的一组150-200kDa质膜蛋白显着过表达。最后，非洲爪蟾卵母细胞注射了来自抗性细胞的mRNA，并与[14C] GCE一起孵育，分泌的放射性标记比对照卵母细胞更快。糖胆酸在该细胞系中的分泌增强与ABC / mdr相关蛋白的过表达有关，其中一些蛋白显然是新的，可能包括胆汁酸转运蛋白。

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