Mechanisms Underlying Proglucagon Gene Expression

The proglucagon gene (gcg) encodes a number of peptide hormones that are of cell-type specifically expressed in the pancreatic islets, the distal ileum and the large intestine, as well as certain brain neuronal cells. These hormones are important in controlling blood glucose homeostasis, intestinal cell proliferation, and satiety. More importantly, the major hormone generated in the pancreas (i.e. glucagon) exerts opposite effects to the ones that are produced in the intestines (i.e. glucagon-like peptide-1 (GLP-1) and GLP-2). To understand the mechanisms underlying cell-type-specific gcg expression may lead to the identification of novel drug targets to control endogenous hormone production for therapeutic purposes. Extensive in vitro examinations have shown that more than a half dozen of homeodomain (HD) proteins are able to interact with the gcg gene promoter and activate its expression. In vivo 'knock-out' mouse studies, however, cannot demonstrate the role of some of them (i.e. Cdx-2, Brn-4, and Nkx6.2) in the development of pancreatic islet alpha-cells, suggesting that these HD proteins may exert some redundant functions in the genesis of gcg-producing cells. Investigations have also revealed that gcg expression is controlled by both protein kinase A and Epac signaling pathways in response to cAMP elevation, and cell-type specifically controlled by insulin and the effectors of the Wnt signaling pathway. This review summarizes our current understanding on the mechanisms underlying gcg transcription and presented my interpretations on how the interactions between different signaling networks regulate gcg expression.