Cooperativity between the Preproinsulin mRNA Untranslated Regions Is Necessary for Glucose-stimulated Translation

Barton Wicksteed, Terence P. Herbert, Cristina Alarcon, Melissa K. Lingohr, Larry G. Moss, Christopher J. Rhodes*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

78 Scopus citations

Abstract

Glucose regulates proinsulin biosynthesis via stimulation of the translation of the preproinsulin mRNA in pancreatic β-cells. However, the mechanism by which this occurs has remained unclear. Using recombinant adenoviruses that express the preproinsulin mRNA with defined alterations, the untranslated regions (UTRs) of the preproinsulin mRNA were examined for elements that specifically control translation of the mRNA in rat pancreatic islets. These studies revealed that the pre-proinsulin 5′-UTR was necessary for glucose stimulation of preproinsulin mRNA translation, whereas the 3′-UTR appeared to suppress translation. However, together the 5′- and 3′-UTRs acted cooperatively to markedly increase glucose-induced proinsulin biosynthesis. In primary hepatocytes the presence of the preproinsulin 3′-UTR led to reduced mRNA levels compared with the presence of the SV40 3′-UTR, consistent with the presence of mRNA stability determinants in the 3′-UTR that stabilize the preproinsulin mRNA in a pancreatic β-cell-specific manner. Translation of these mRNAs in primary hepatocytes was not stimulated by glucose, indicating that regulated translation of the preproinsulin mRNA occurs in a pancreatic β-cell-specific manner. Thus, the untranslated regions of the preproinsulin mRNA play crucial roles in regulating insulin production and therefore glucose homeostasis by regulating the translation and the stability of the preproinsulin mRNA.

Original languageEnglish (US)
Pages (from-to)22553-22558
Number of pages6
JournalJournal of Biological Chemistry
Volume276
Issue number25
DOIs
StatePublished - Jun 22 2001

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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