Control of Peptide Hormone Biosynthesis by PC2 and 7B2

肽激素的合成涉及一系列酶促步骤，从激素原转化酶1和2 （PC1和PC2）对前体的蛋白水解裂解开始。近年来，这些酶在细胞内运输过程中通过与结合蛋白的相互作用来调节。例如，PC2结合神经内分泌特异性的低分子量蛋白7B2，最近的数据表明PC1也具有结合蛋白proSAAS。这两种蛋白都存在于迄今为止检测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。在之前的资助期内，我们定义了PC2/7B2相互作用的细胞生物学和生物化学。在与Philip Leder博士的合作中，我们还描述了7B2空小鼠，它会发展成致命的库欣病；这是相当令人惊讶的，因为没有PC2的动物没有表现出类似疾病的迹象。在本次更新申请中，我们建议将7B2的研究扩展到放置在同一小鼠品系CJ57BL/6J中的7B2和PC2 null的比较。为了解释7B2在垂体ACTH高分泌中的作用，我们将从垂体/肾上腺轴的内分泌学角度比较这两种空白动物，重点是a) ACTH生物合成和释放的差异；B)多巴胺能系统的电位差异调节；c)超微结构水平的电位差。在最后一个具体目标中，我们建议继续我们对PC1结合蛋白proSAAS的研究。我们将确定该蛋白的生物合成途径，进行结构-功能分析，并确定其与7B2/PC2系统的异同。PC1和PC2被认为是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和转化酶结合蛋白在分泌细胞中的作用，与糖尿病和其他肽激素合成异常的疾病（如库欣病和纳尔逊病）有关；神经内分泌癌。

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.