Somatostatin is an important regulator of pancreatic, pituitary, gastrointestinal, and neuronal function. The overall objective of this proposal is to elucidate the molecular biological mechanisms underlying the biosynthesis and processing of prosomatostatin, the precursor of somatostatin. The specific issues which will be addressed concern the regulation of somatostatin production at the transcriptional, translational, and post-translational levels. These issues will be studied using two different biological models -- the anglerfish, which expresses a multigene family of somatostatin-like peptides, and the rat, which appears to have a single somatostatin gene. To accomplish our objective, we will first determine the role of the pro-region sequences of prosomatostatin in directing precursor processing. To do this, we will characterize the products expressed by endocrine and neuronal cells transfected with the anglerfish and rat pre-prosomatostatin cDNAs. We will also determine whether precise conservation of the pro-region is required for processing to somatostatin-28 and -14. Factors which regulate somatostatin gene transcription will be identified using primary cultures of brain cells and lines of somatostatin-producing cells. Regulation of gene transcription will be further studied using cell lines transfected with the cloned rat somatostatin gene. An understanding of the events involved in somatostatin synthesis at the molecular level has important implications for nearly all aspects of endocrine physiology. This understanding may also provide insights relevant to specific diseases such as diabetes mellitus and Alzheimer's dementia.
| Sevarino, K A; Stork, P (1991) Multiple preprosomatostatin sorting signals mediate secretion via discrete cAMP- and tetradecanoylphorbolacetate-responsive pathways. J Biol Chem 266:18507-13 |
| Sevarino, K A; Ventimiglia, R; Stork, P (1990) Processing and intracellular sorting of anglerfish and rat preprosomatostatins in mammalian endocrine cells. Metabolism 39:26-9 |
| Sevarino, K A; Stork, P; Ventimiglia, R et al. (1989) Amino-terminal sequences of prosomatostatin direct intracellular targeting but not processing specificity. Cell 57:11-9 |
