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
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