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首页> 外文期刊>Journal of neuroendocrinology >Mutant and misfolded human growth hormone is rapidly degraded through the proteasomal degradation pathway in a cellular model for isolated growth hormone deficiency type II.
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Mutant and misfolded human growth hormone is rapidly degraded through the proteasomal degradation pathway in a cellular model for isolated growth hormone deficiency type II.

机译：在分离的II型生长激素缺乏症的细胞模型中，突变和错误折叠的人类生长激素通过蛋白酶体降解途径迅速降解。

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摘要

Autosomal dominant isolated growth hormone deficiency type II (IGHD II) is mainly caused by splice site mutations of the GH-1 gene, leading to deletion of amino acids 32-71 of the human growth hormone (hGH). The severe hGH deficit in IGHD II suggests a dominant negative effect of the partially deleted del(32-71)-hGH on the production, storage or secretion of normal wild-type (wt)-hGH in somatotrophic cells of the pituitary. To shed more light on the cellular and molecular basis of IGHD II, we established and analysed diverse clones of the rat somatotrophic cell line GH(4)C(1) stably expressing either wt-hGH, del(32-71)-hGH, or both proteins concomitantly. The cellular morphology of all transfected GH(4)C(1) cell clones showed moderate differences to untransfected GH(4)C(1) cells. On the molecular level, both cDNA-constructs induced transcription but, under normal culture conditions, only wt-hGH protein was found to be synthesised and secreted in readily detectable amounts. By contrast, only after inhibition of proteasomes did high amounts of del(32-71)-hGH show up. The solubility of del(32-71)-hGH in nondenaturing buffer was poor compared to wt-hGH, hinting at molecular aggregation, and several epitopes recognised by monoclonal hGH antibodies were not present on del(32-71)-hGH, confirming the assumption that del(32-71)-hGH must be severely misfolded. Expression of both proteins in Escherichia coli mirrored the findings from the GH(4)C(1) cell clones in terms of solubility and immunological reactivity. The results of the present study indicate that, in IGHD II, somatotrophs continuously have to remove misfolded del(32-71)-hGH via the proteasomal degradation pathway, suggesting a mechanism that may result in chronic cellular stress.
机译：常染色体显性遗传性孤立生长激素缺乏症II型（IGHD II）主要由GH-1基因的剪接位点突变引起，导致人类生长激素（hGH）氨基酸32-71缺失。 IGHD II中严重的hGH缺乏表明，部分缺失的del（32-71）-hGH对垂体生长细胞中正常野生型（wt）-hGH的产生，储存或分泌具有显着的负作用。为了进一步了解IGHD II的细胞和分子基础，我们建立并分析了稳定表达wt-hGH，del（32-71）-hGH的大鼠体营养细胞系GH（4）C（1）的各种克隆。或两种蛋白质同时出现。所有转染的GH（4）C（1）细胞克隆的细胞形态显示中等差异到未转染的GH（4）C（1）细胞。在分子水平上，两种cDNA均可诱导转录，但在正常培养条件下，仅wt-hGH蛋白被合成并以易于检测的量分泌。相反，仅在抑制蛋白酶体后才出现大量的del（32-71）-hGH。与wt-hGH相比，del（32-71）-hGH在非变性缓冲液中的溶解度差，提示分子聚集，并且del（32-71）-hGH上不存在单克隆hGH抗体识别的几个表位，这证实了假设必须严重错误折叠del（32-71）-hGH。两种蛋白质在大肠杆菌中的表达反映了从GH（4）C（1）细胞克隆的溶解度和免疫反应性方面的发现。本研究的结果表明，在IGHD II中，体营养动物必须通过蛋白酶体降解途径连续清除错误折叠的del（32-71）-hGH，提示其可能导致慢性细胞应激。

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