Regulation of parathyroid hormone mRNA stability by calcium, phosphate and uremia

Abstract

This review focuses on the regulation of parathyroid hormone gene expression by dietary-induced hypocalcemia, hypophosphatemia and uremia. Understanding the mechanism by which calcium and phosphate regulate parathyroid hormone gene expression is important for both normal physiology and in pathological states, especially chronic kidney disease. Calcium and phosphate regulate parathyroid hormone secretion, gene expression and, if prolonged, parathyroid cell proliferation. Chronic kidney disease is characterized by a high serum phosphate level that often leads to secondary hyperparathyroidism. In the rat, regulation of parathyroid hormone gene expression by calcium, phosphate and uremia is posttranscriptional, affecting mRNA stability. Differences in binding of protective trans-acting proteins to a conserved protein-binding cis-acting instability element in the parathyroid hormone mRNA 3'-untranslated region alter parathyroid hormone mRNA stability. Two trans-acting proteins - adenosine-uridine rich binding factor 1 and Up-stream of N-ras- stabilize parathyroid hormone mRNA in vivo and in vitro. Parathyroid hormone mRNA also interacts with mRNA decay-promoting proteins and ribonucleases that lead to parathyroid hormone mRNA degradation. Calcium, phosphate and uremia determine parathyroid hormone mRNA stability through the binding of the protective factors adenosine-uridine rich binding factor 1 and Up-stream of N-ras and the recruitment of a degradation complex that cleaves parathyroid hormone mRNA.