Chronic hepatitis, hepatocyte fragility, and increased soluble phosphoglycokeratins in transgenic mice expressing a keratin 18 conserved arginine mutant.
Chronic hepatitis, hepatocyte fragility, and increased soluble phosphoglycokeratins in transgenic mice expressing a keratin 18 conserved arginine mutant.
复制标题
DOI：
10.1083/jcb.131.5.1303
复制
发表时间：
1995-12
期刊：
影响因子：
--
通讯作者：
Omary MB
中科院分区：
文献类型：
--
作者：
Ku NO;Michie S;Oshima RG;Omary MB
腺上皮中两种主要的中间丝蛋白是角蛋白多肽 8 和 18 (K8/18)。为了评估 K18 的功能和潜在的疾病关联，我们检查了 K18 高度保守的精氨酸 (arg89) 突变的影响。与野生型 K8/18 表达后获得的典型丝相比，K18 arg89-->his/cys 及其正常 K8 伴侣在培养细胞中的表达导致点状染色。 Generation of transgenic mice expressing human K18 arg89-->cys resulted in marked disruption of liver and pancreas keratin filament networks.最突出的组织学异常是年轻时出现的肝脏炎症和坏死，与肝细胞脆性和血清转氨酶升高有关。这些效应是由突变引起的，因为表达野生型人类 K18 的转基因小鼠表现出正常的表型。在体外和表达突变型 K18 的转基因动物中还注意到，去污剂溶解的 K8/18 的磷酸化和糖基化相对增加。我们的结果表明，高度保守的 arg 在腺角蛋白组织和组织脆性中发挥着重要作用，正如表皮角蛋白所描述的那样。 arg 突变角蛋白的磷酸化和糖基化改变可能解释了这些蛋白质的细胞功能的一些潜在变化。 Mice expressing mutant K18 provide a novel animal model for human chronic hepatitis, and for studying the tissue specific function(s) of K8/18.
The two major intermediate filament proteins in glandular epithelia are keratin polypeptides 8 and 18 (K8/18). To evaluate the function and potential disease association of K18, we examined the effects of mutating a highly conserved arginine (arg89) of K18. Expression of K18 arg89-->his/cys and its normal K8 partner in cultured cells resulted in punctate staining as compared with the typical filaments obtained after expression of wild-type K8/18. Generation of transgenic mice expressing human K18 arg89-->cys resulted in marked disruption of liver and pancreas keratin filament networks. The most prominent histologic abnormalities were liver inflammation and necrosis that appeared at a young age in association with hepatocyte fragility and serum transaminase elevation. These effects were caused by the mutation since transgenic mice expressing wild-type human K18 showed a normal phenotype. A relative increase in the phosphorylation and glycosylation of detergent solubilized K8/18 was also noted in vitro and in transgenic animals that express mutant K18. Our results indicate that the highly conserved arg plays an important role in glandular keratin organization and tissue fragility as already described for epidermal keratins. Phosphorylation and glycosylation alterations in the arg mutant keratins may account for some of the potential changes in the cellular function of these proteins. Mice expressing mutant K18 provide a novel animal model for human chronic hepatitis, and for studying the tissue specific function(s) of K8/18.