BIOSYNTHESIS OF SOMATOSTATIN

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.