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失衡:部分角蛋白10基因敲除的后果

Out of balance: consequences of a partial keratin 10 knockout.

作者信息

Reichelt J, Bauer C, Porter R, Lane E, Magin V

机构信息

Institüt für Genetik, Friedrich-Wilhelms-Universität, Bonn, Germany.

出版信息

J Cell Sci. 1997 Sep;110 ( Pt 18):2175-86. doi: 10.1242/jcs.110.18.2175.

Abstract

Recently we generated keratin 10 knockout mice which provided a valuable model for the dominantly inherited skin disorder epidermolytic hyperkeratosis. Here we investigated the molecular basis for their phenotype. Hetero- and homozygotes expressed a truncated keratin 10 peptide which has been identified directly by microsequencing. Epitope mapping of monoclonal antibodies to keratin 10T enabled us to study its distribution relative to keratin 6, which is highly expressed in keratin 10 knockout mice, by double-immunogold electron microscopy. This revealed that keratin 10T was restricted to complexes with keratin 1 but did not mix with keratin 6. The latter did not form extended filaments with keratins 16/17 but aggregates. Keratins 6/16 were unable to compensate for the lack of normal keratin 1/10 filaments. Remarkably keratin 6 aggregates strictly colocalized with keratohyalin granules. Residual keratin 1/10T clumps were located in the cell periphery and at desmosomes which maintained a normal architecture. Surprisingly keratin 2e, a keratin tailored to sustain mechanical stress, was completely lost in paw sole epidermis of homozygous keratin 10 knockout mice, pointing to keratin 10 as its partner. The selective pairing of keratin 10T and the loss of keratin 2e indicate that in vivo keratins are less promiscuous than in vitro. Skin fragility in keratin 10 knockout mice and in epidermolytic hyperkeratosis is probably the consequence of two complementing mechanisms namely a decrease of normal keratin 1/10 filaments and an increase in keratins 6/16 with a poor filament-forming capacity.

摘要

最近我们培育出了角蛋白10基因敲除小鼠,这为显性遗传性皮肤病——表皮松解性角化过度症提供了一个有价值的模型。在此我们研究了其表型的分子基础。杂合子和纯合子表达一种截短的角蛋白10肽段,该肽段已通过微量测序直接鉴定。针对角蛋白10T的单克隆抗体的表位作图,使我们能够通过双免疫金电子显微镜研究其相对于角蛋白6的分布,角蛋白6在角蛋白10基因敲除小鼠中高度表达。这表明角蛋白10T局限于与角蛋白1形成复合物,而不与角蛋白6混合。角蛋白6不与角蛋白16/17形成延伸的细丝,而是形成聚集体。角蛋白6/16无法弥补正常角蛋白1/10细丝的缺失。值得注意的是,角蛋白6聚集体与透明角质颗粒严格共定位。残留的角蛋白1/10T团块位于细胞周边和维持正常结构的桥粒处。令人惊讶的是,角蛋白2e这种为承受机械应力而特化的角蛋白,在纯合角蛋白10基因敲除小鼠的爪底表皮中完全缺失,这表明角蛋白10是其伙伴。角蛋白10T的选择性配对以及角蛋白2e的缺失表明,在体内角蛋白比在体外更具特异性。角蛋白10基因敲除小鼠和表皮松解性角化过度症中的皮肤脆性,可能是两种互补机制的结果,即正常角蛋白1/10细丝减少以及角蛋白6/16增加且细丝形成能力较差。

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