Malcolm J. Low

Tissue-specific posttranslational processing of pre-prosomatostatin encoded by a metallothionein-somatostatin fusion gene in transgenic mice

The somatostatins are neuropeptides of 14 and 28 amino acids that inhibit the release of growth hormone and other hypophyseal and gastrointestinal peptides. These neuropeptides are cleaved posttranslationally from a common precursor, pre-prosomatostatin. We report here the production and processing of pre-prosomatostatin by transgenic mice carrying a metallothionein-somatostatin fusion gene. The most active site of somatostatin production, as determined by hormone concentrations in the tissues, is the anterior pituitary, a tissue that does not normally synthesize somatostatin-like peptides. Anterior pituitary processed pre-prosomatostatin almost exclusively to the two biologically active peptides, somatostatin-14 and somatostatin-28, whereas the liver and kidney synthesized much smaller quantities of predominantly a 6000 dalton somatostatin-like peptide. The growth of the transgenic mice was normal despite high plasma levels of the somatostatin-like peptides. These studies indicate that proteases which cleave prosomatostatin to somatostatin-28 and somatostatin-14 are not specific to tissues that normally express somatostatin.

Somatostatin gene regulation: An overview

The somatostatinergic system has proven to be one of the best models of neuropeptide biology. Originally characterized as a hypothalamic regulator of growth hormone secretion, somatostatin also regulates the secretion of several other pituitary, pancreatic, and gastrointestinal (GI) hormones including thyrotropin-stimulating hormone, insulin, glucagon, and gastrin. Disorders in somatostatin metabolism have been proposed to contribute to the pathogenesis of Alzheimers disease, epilepsy, GI motility disorders, and diabetes. On a more basic level, studies of somatostatin action have integrated divergent concepts of intracellular signal transduction. Advances in the understanding of somatostatin biosynthesis have had an impact on areas outside the field of endocrinology by providing new concepts of eukaryotic gene regulation. This report focuses on the transcriptional regulation of somatostatin gene expression. Two aspects of somatostatin gene transcription will be considered--regulated expression by second messengers and tissue-specific basal expression.

The Somatostatin Genes

Somatostatin (somatotropin-release inhibiting factor; SRIF) was originally named for its ability to inhibit the release of growth hormone from cultured rat pituitary cells (1). Like the names of many other regulatory peptides, the designation SRIF proved to be far too limited. In addition to inhibiting the release of pituitary growth hormone (2,3), somatostatin inhibits the release of thyrotropin (3–6) and, in certain circumstances, prolactin (7) and adrenocorticotropin (8). Somatostatin appears to regulate the secretion of the pancreatic-islet hormones glucagon (9) and insulin (10) and to have a number of effects on gastrointestinal function. These gastrointestinal effects include inhibition of the secretion of gut hormones (gastrin, pancreozymin, pancreatic polypeptide, vasoactive intestinal peptide, glucagon, motilin, gastric inhibitory peptide, secretin), exocrine secretion (gastric acid, pancreatic bicarbonate, gastric and pancreatic enzymes), gastrointestinal motility (gastric emptying, gallbladder contraction), absorption, and blood flow (reviewed in 11). Finally, somatostatin influences the release of the neurotransmitters acetylcholine (12), norepinephrine (13), and serotonin (14) and acts as a neurotransmitter itself (15).

Biosynthesis of Somatostatin, Vasoactive Intestinal Polypeptide, and Thyrotropin Releasing Hormone

The purpose of this review is to describe the recent advances in our understanding of the biosynthesis of three brain/gut peptides — somatostatin, vasoactive intestinal polypeptide, and thyrotropin releasing hormone. Although each of these hormones is found in both the brain and gastrointestinal tract, their physiology is quite distinct. Furthermore, each peptide poses a unique set of problems for isolating and characterizing its gene and gene products. This review focuses on the different molecular approaches that we have used to characterize the precursors of these three peptides. It further describes the more general techniques that we are currently using to examine the expression of the three genes.