Exp Clin Endocrinol Diabetes 2004; 112 - V53
DOI: 10.1055/s-2004-819100

Stabilization of mRNA by PTB promotes the biogenesis of insulin secretory granules

KP Knoch 1, H Bergert 2, B Borgonovo 1, HD Saeger 2, A Altkrüger 1, P Verkade 3, M Solimena 1
  • 1Experimental Diabetology
  • 2Dept. of Surgery, Medical School, TU Dresden
  • 3Max Planck Institute for Molecular Cell Biology and Genetics Dresden

Glucose stimulation of pancreatic ß-cells triggers the exocytosis of insulin secretory granules (SGs) and the rapid biosynthesis of new SGs. The glucose-stimulated pathway responsible for upregulating the expression of SG components in a coordinated fashion has so far been unknown. We have now found that mRNAs encoding many SG components (ICA512, PC1/3, PC2, chromogranins, etc.), similar to insulin, contain a consensus motif for the binding of polypyrimidine tract binding protein (PTB) in their 3’-UTR. Binding of PTB to this consensus is glucose-stimulated, occurs very rapidly following stimulation (<2 hrs) and results in the stabilization of these mRNAs. This stabilization, on the other hand, was not observed in the case of carboxypeptidase E (CPE), whose expression is not glucose-regulated and whose mRNA lacks the consensus for PTB binding. Glucose stimulation prompts the translocation of PTB from the nucleus to the cytoplasmic compartment, where stabilization of mRNA by PTB could contribute to the increased translation of SG proteins. Accordingly, down-regulation of PTB expression in insulinoma INS-1 cells by RNA intererference dramatically reduces the expression of most SG proteins, but not of CPE or other control proteins, and causes the virtual disappearance of SGs. Thus, we have uncovered a post-transcriptional mechanism that allows pancreatic ß-cells to quickly restore their pool of SGs in response to stimulation. As newly formed SGs are preferentially recruited for exocytosis, this pathway may have a profound impact on the ability of ß-cells, and possibly other neuroendocrine cells, to modulate hormone secretion.