Comparative Analysis of Insulin Gene Promoters: Implications for Diabetes Research

Colin W. Hay; Kevin Docherty

Disclosures

Diabetes. 2006;55(12):3201-3213. 

In This Article

Sequence Elements That are Absent From The Human Insulin Promoter

CCAAT Box

Several of the descriptions of the effects of transcription factors on insulin expression are based on results from single species. For example, there is a transcriptionally active CCAAT regulatory element that overlaps the single CRE site in the insulin promoters of both rat and mouse. Expression studies using rat insulin 1 promoter have shown that the combined CRE/CCAAT site shows preferential binding for the nuclear transcription factor-Y (NF-Y), which leads to reduced influence of CRE-associated signaling.[116] A search of the other insulin promoters revealed not only that no nonrodent species have a CCAAT site that overlaps with CRE, but that CCAAT sites are totally absent from all of the insulin promoters except zebrafish, which has three at –164, –130, and –85. Therefore, NF-Y signaling, which has an absolute requirement for all five bases in the CCAAT consensus sequence,[117] is unique to rodents within mammals and does not typically play a role in insulin regulation.

HNF-4α Regulatory Element

Rat and mouse insulin 1 and 2 promoters contain a consensus binding site for HNF-4α (5'ACGGCAAAGTCC) located between –69 and –57. The rat insulin 1 promoter has been shown to be activated directly by HNF-4α, which can interact synergistically with PDX-1 at the adjacent A1 site.[118] In contrast, the HNF-4α binding site does not exist in the human insulin promoter, and HNF-4α fails to activate the gene in reporter assays.[72] A search of all other insulin promoters found no evidence of any HNF-4α binding sites. Therefore, HNF-4α transactivation is unique to rodents and does not generally have a function in insulin regulation.

STAT Regulatory Element

Hormones involved in energy homeostasis and growth (e.g., leptin, prolactin, and growth hormone) have been reported to modify rat insulin 1 expression at –330 to –322 (5'TTCTGGGAA) through the transcription factors STAT3.[119] and STAT5.[120] Examination of all insulin promoters revealed that the STAT regulatory element is present only in the rat insulin 1 promoter, although the other rodent insulin promoters have only a single base pair substitution within the consensus sequence. The differences in the human insulin promoter were much greater, raising uncertainty about the relevance of direct influence by the STAT signaling pathways on insulin expression in humans.

COUP-TFII Binding Element

Chicken ovalbumin upstream promoter–transcription factor II (COUP-TFII), which is also known as NR2F and ARP-1, binds a direct repeat in the chicken ovalbumin promoter.[121] and has been reported to bind an unrelated imperfect repeat in rat insulin 2 promoter between –55 and –38 (5'GGGTCAGGGGGGGGGTGC).[122] through a different molecular mechanism.[123] COUP-TFII has recently been implicated in the control of blood glucose in heterozygous knockout transgenic mice that had increased insulin secretion in low glucose and decreased insulin secretion in high glucose.[124] The corresponding regions in human and all primates (5'AGGTAGGGGAGATGGGCT) have several nucleotide differences that result in loss of essential guanine nucleotides. In rat insulin 1 and both mouse insulin promoters, there are transitions of essential guanines to adenines in positions where either purine can serve for recognition, if not intermolecular association. Given the irregular binding affinities of COUP-TFII, it is difficult to make unequivocal statements regarding its possible effects on these insulin promoters. The other mammals (cow, dog, and pig) have deletions in the COUP-TFII binding region, and no known form of consensus sequences are to be found in chicken and zebrafish insulin promoters. Within the context of this survey, the action of this COUP-TFII would seem to be limited to rodents.

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