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: 7014497
• 负责人: IRIS LINDBERG
• 金额: $ 29.57万
• 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 2008-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7014497
• 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.

肽激素的合成涉及多个酶促步骤，从蛋白水解裂解开始，前体蛋白水解裂解1和2（PC1和PC2）。近年来，显然，这些酶本身受细胞内运输过程中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，并且最近的数据表明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，这表明对神经内分泌表型有重要贡献。在上一个资金期间，我们定义了PC2/7B2相互作用的细胞生物学和生物化学。我们还与菲利普·莱德（Philip Leder）博士合作，我们还表征了7B2 Null Mouse，该老鼠发展出一种致命的库欣氏病。鉴于PC2无动物没有类似疾病的迹象，这是令人惊讶的。在此续签应用中，我们建议将对7B2的研究扩展到将相同小鼠菌株CJ57BL/6J的7B2和PC2无效的比较。为了解释7B2在垂体ACTH的过度分泌中的作用，我们将比较这两种无效的动物相对于垂体/肾上腺轴的内分泌学，重点是A）ACTH生物合成和释放的差异； b）多巴胺能系统的潜在差异调节； c）超微结构水平的潜在差异。在最后一个特定目标中，我们建议继续对PC1结合蛋白Prosaas的研究。我们将定义该蛋白质的生物合成途径，执行结构功能分析，并定义与7B2/PC2系统的相似性差异。 PC1和PC2被认为代表了负责胰腺胰腺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结合蛋白的生理和生物化学，并将这些发现扩展到其他转化酶。更好地了解转化酶的调节以及转化酶结合蛋白在分泌细胞中的作用与糖尿病和其他疾病有关，其中肽激素合成是异常的，例如Cushing和Nelson的疾病。和神经内分泌癌。