Control of Peptide Hormone Biosynthesis by PC2 and 7B2

PC2 和 7B2 对肽激素生物合成的控制

• 批准号: 6477622
• 负责人: IRIS LINDBERG
• 金额: $ 31.05万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-09-15 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6477622
• 关键词: Adenoviridae; Cushing's syndrome; adrenal disorder; adrenocorticotropic hormone; binding proteins; corticosterone; disease /disorder model; dopamine; enzyme activity; gene deletion mutation; gene targeting; genetically modified animals; hormone binding protein; laboratory mouse; peptide hormone biosynthesis; pituitary disorders; prohormone convertase; proopiomelanocortin; protein protein interaction; protein structure function; site directed mutagenesis; tissue /cell culture; transfection /expression vector

The synthesis of peptide hormones involves a number of enzymatic steps beginning with proteolytic cleavage of precursors by prohormone convertases 1 and 2 (PC1 and PC2). In recent years it has become apparent that these enzymes are themselves regulated by interaction with binding proteins during transport within the cell. For example, PC2 binds the neuroendocrine-specific, low molecular weight protein 7B2, and very recent data indicate that PC1 also possesses a binding protein, proSAAS. Both of these proteins are present in all neuroendocrine cell types examined to date, suggesting important contributions to the neuroendocrine phenotype. In the previous funding period we defined the cell biology and the biochemistry of the PC2/7B2 interaction. In collaboration with Dr. Philip Leder, we also characterized the 7B2 null mouse, which develops a lethal form of Cushing's disease; this was quite surprising in light of the fact that the PC2 null animal exhibits no signs of similar illness. In this renewal application, we propose to extend our studies on 7B2 to the comparison of the 7B2 and PC2 nulls placed in the same mouse strain, CJ57BL/6J. In an effort to explain the role of 7B2 in the hypersecretion of pituitary ACTH, we will compare these two null animals with respect to the endocrinology of the pituitary/adrenal axis, focusing on a) differences in ACTH biosynthesis and release; b) potential differential modulation by dopaminergic systems; and c) potential differences at the ultrastructural level. In the last specific aim, we propose to continue our studies of the PC1 binding protein, proSAAS. We will define the biosynthetic pathway of this protein, perform structure-function analysis, and define similarities aril differences with the 7B2/PC2 system. PC1 and PC2 are thought to represent the chief enzymes responsible for the pancreatic hormones glucagon and insulin as well as many other peptide hormones. The long-term goal of these studies is to describe the physiology and biochemistry of the PC1 and PC2-binding proteins and to extend these findings to other convertases. A better understanding of the regulation of convertases and the roles of convertase binding proteins in secretory cells is relevant to diabetes and other diseases in which peptide hormone synthesis is abnormal, such as Cushing's and Nelson's diseases; and neuroendocrine carcinoma.

肽激素的合成涉及许多酶促步骤，首先是激素原转化酶 1 和 2（PC1 和 PC2）对前体进行蛋白水解裂解。近年来，越来越明显的是，这些酶本身在细胞内运输过程中受到与结合蛋白相互作用的调节。例如，PC2 结合神经内分泌特异性低分子量蛋白 7B2，最近的数据表明 PC1 还具有结合蛋白 proSAAS。这两种蛋白质都存在于迄今为止检查的所有神经内分泌细胞类型中，表明对神经内分泌表型有重要贡献。在之前的资助期间，我们定义了 PC2/7B2 相互作用的细胞生物学和生物化学。我们与 Philip Leder 博士合作，还鉴定了 7B2 缺失小鼠的特征，该小鼠会患上致命的库欣病。鉴于 PC2 缺失的动物没有表现出类似疾病的迹象，这是相当令人惊讶的。在此更新申请中，我们建议将我们对 7B2 的研究扩展到同一小鼠品系 CJ57BL/6J 中的 7B2 和 PC2 null 的比较。为了解释 7B2 在垂体 ACTH 分泌过多中的作用，我们将比较这两种无效动物的垂体/肾上腺轴内分泌学，重点关注 a) ACTH 生物合成和释放的差异； b) 多巴胺能系统的电位差动调制； c) 超微结构水平上的电位差异。在最后一个具体目标中，我们建议继续研究 PC1 结合蛋白 proSAAS。我们将定义该蛋白质的生物合成途径，进行结构功能分析，并定义与 7B2/PC2 系统的相似点和差异。 PC1 和 PC2 被认为代表负责胰腺激素胰高血糖素和胰岛素以及许多其他肽激素的主要酶。这些研究的长期目标是描述 PC1 和 PC2 结合蛋白的生理学和生物化学，并将这些发现扩展到其他转化酶。更好地了解分泌细胞中转化酶的调节和转化酶结合蛋白的作用与糖尿病和其他肽激素合成异常的疾病有关，例如库欣病和尼尔森病；和神经内分泌癌。