Insulin gene: organisation, expression and regulation.
Insulin, a major hormone of the endocrine pancreas, plays a key role in the control of glucose homeostasis. This review discusses the mechanisms of cell-specific expression and regulation of the insulin gene. Whereas expression is restricted to islet beta-cells in adults, the insulin gene is more widely expressed at several embryonic stages, although the role of extrapancreatic expression is still unclear. beta-cell-specific expression relies on the interactions of 5'-flanking sequence motifs of the promoter with a number of ubiquitous and islet-specific transcription factors. IEF1 and IPF-1, by their binding to the E and A boxes, respectively, of the insulin gene promoter, appear to be the major determinants of beta-cell-specific expression. IEF1 is a heterodimer of the basic helix-loop-helix family of transcription factors, whereas IPF-1 belongs to the homeodomain-containing family. beta-cell specific determinants are conserved throughout evolution, although the human insulin gene 5'-flanking sequence also contains a polymorphic minisatellite which is unique to primates and may play a role in insulin gene regulation. Glucose modulates insulin gene transcription, with multiple elements of the promoter involved in glucose responsiveness. Remarkably, IPF-1 and IEF1 are involved in both beta-cell-specific expression and glucose regulation of the insulin gene. cAMP also regulates insulin gene transcription through a CRE, in response to various hormonal stimuli. On the whole, recent studies have provided a better understanding of beta-cell differentiation and function.
Dumonteil
E
E
Diabétologie Clinique, Centre Médical Universitaire, Geneva, Switzerland.
Philippe
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J
D000328:Adult; D000818:Animals; D001483:Base Sequence; D000242:Cyclic AMP / Q000502:physiology; D005314:Embryonic and Fetal Development; D005786:Gene Expression Regulation / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D005947:Glucose / Q000502:physiology; D006801:Humans; D007328:Insulin / Q000235:genetics*; D007515:Islets of Langerhans / Q000378:metabolism; D008969:Molecular Sequence Data
D007328:Insulin; D000242:Cyclic AMP; D005947:Glucose