Tissue‐Specific regulation of glucokinase gene expression

Abstract

Glucokinase contributes to the maintenance of blood glucose homeostasis by catalyzing the high K_m phosphorylation of glucose in the liver and the pancreatic β cell, the only two tissues known to express this enzyme. Molecular biological studies of the glucokinase gene and its products have advanced our understanding of how this gene is differentially regulated in the liver and β cell. The production of an active glucokinase isoform is determined by both transcriptional and post‐transcriptional events. Two different promoter regions that are widely separated in a single glucokinase gene are used to produce glucokinase mRNAs in the liver, pancreatic β cell, and pituitary. The different transcription control regions are tissue‐specific in their expression and are differentially regulated. In liver, glucokinase gene expression is regulated by insulin and cAMP, whereas in the β cell it is regulated by glucose. The upstream glucokinase promoter region, which gives rise to the glucokinase mRNA in pituitary and pancreas, is structurally and functionally different from the downstream promoter region, which gives rise to the glucokinase mRNA in liver. The use of distinct promoter regions in a single glucokinase gene enables a different set of transcription factors to be utilized in the liver and islet, thus allowing a functionally similar gene product to be regulated in a manner consistent with the different functions of these two tissues. In addition, the splicing of the glucokinase pre‐mRNA is regulated in a tissue‐specific manner and can affect the activity of the gene product. This is most apparent in the pituitary where an alternately spliced glucokinase mRNA is produced that does not encode a functional enzyme due to an introduced frameshift.