Control of Peptide Hormone Biosynthesis by PC2 and 7B2

多肽激素的合成涉及许多酶促步骤，从蛋白质分解开始。 前体被前激素转换酶1和2(PC1和PC2)切割。近年来，它已经成为 显然，这些酶本身受运输过程中与结合蛋白的相互作用的调节 在细胞内。例如，PC2结合神经内分泌特异的低分子蛋白7B2，以及 最近的数据表明，PC1还拥有一种结合蛋白--proSAAS。这两种蛋白质都是 目前在所有神经内分泌细胞类型中都存在，这表明在 神经内分泌表型。在之前的资助期间，我们定义了细胞生物学和生物化学 PC2/7B2相互作用。在与菲利普·莱德博士的合作中，我们还对7B2零鼠标进行了表征， 这会发展成一种致命的库兴氏病；考虑到PC2为空的事实，这是相当令人惊讶的 动物没有表现出类似疾病的迹象。 在今次的续期申请中，我们建议将7B2的研究扩展至7B2和7B2的比较。 将PC2空质粒置于相同品系CJ57BL/6J中。为了解释7B2在细胞周期中的作用 垂体ACTH的高分泌，我们将比较这两种空白动物在内分泌学方面的差异 垂体轴/肾上腺轴，关注a)ACTH生物合成和释放的差异；b)电位差异 多巴胺能系统的调节；以及c)超微结构水平上的电位差异。在最后一个具体的例子中 目的：继续我们对PC1结合蛋白proSAAS的研究。我们将定义生物合成 这种蛋白质的途径，进行结构-功能分析，并定义与 7B2/PC2系统。 PC1和PC2被认为是负责胰腺激素的主要酶。 胰高血糖素和胰岛素以及许多其他多肽荷尔蒙。这些研究的长期目标是 描述PC1和PC2结合蛋白的生理和生化，并将这些发现推广到 更好地理解转换酶的调节和转换酶结合的作用 分泌细胞中的蛋白质与糖尿病和其他疾病有关，在这些疾病中，肽激素的合成是 异常，如库欣和纳尔逊病；以及神经内分泌癌

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 and 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