Short-term regulation of insulin gene transcription by glucose

Whereas short-term regulation of insulin biosynthesis at the level of translation is well accepted, glucose-dependent transcriptional control is still believed to be a long-term effect occurring after more than 2 hr of glucose stimulation. Because pancreatic β cells are exposed to elevated glucose levels for minutes rather than hours after food uptake, we hypothesized the existence of a short-term transcriptional control. By studying the dynamics of newly synthesized (prepro)insulin RNA and by employing on-line monitoring of gene expression in single, insulin-producing cells, we were able to provide convincing evidence that insulin gene transcription indeed is affected by glucose within minutes. Exposure of insulinoma cells and isolated pancreatic islets to elevated glucose for only 15 min resulted in a 2- to 5-fold elevation in (prepro)insulin mRNA levels within 60–90 min. Similarly, insulin promoter-driven green fluorescent protein expression in single insulin-producing cells was significantly enhanced after transient glucose stimulation. Thus, short-term signaling, such as that involved in insulin secretion, also may regulate insulin gene transcription.

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Short-term regulation of insulin gene transcription

Biochemical Society Transactions ◽

10.1042/bst0300312 ◽

2002 ◽

Vol 30 (2) ◽

pp. 312-317 ◽

Cited By ~ 18

Author(s):

B. Leibiger ◽

T. Moede ◽

S. Uhles ◽

P.-O. Berggren ◽

I. B. Leibiger

Keyword(s):

Insulin Secretion ◽

Gene Transcription ◽

Insulin Gene ◽

Current View ◽

Β Cells ◽

Pancreatic Β Cells ◽

Short Term ◽

Major Nutrient ◽

Glucose Metabolites ◽

Insulin Gene Transcription

Short-term regulation of insulin gene transcription is still a matter of debate. However, an increasing body of evidence shows that insulin gene transcription is affected by signals, such as incretins, glucose metabolites, intracellular Ca2+, and by insulin secreted from pancreatic β-cells, all supporting the concept of an immediate response resulting in insulin gene transcription following food-uptake. The present review aims to summarize the current view on the mechanisms underlying the up-regulation of insulin gene transcription in response to glucose, the major nutrient factor in insulin secretion and biosynthesis.

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Glucose-stimulated Insulin Biosynthesis Depends on Insulin-stimulated Insulin Gene Transcription

Journal of Biological Chemistry ◽

10.1074/jbc.m005216200 ◽

2000 ◽

Vol 275 (39) ◽

pp. 30153-30156 ◽

Cited By ~ 56

Author(s):

Barbara Leibiger ◽

Karin Wåhlander ◽

Per-Olof Berggren ◽

Ingo B. Leibiger

Keyword(s):

Gene Transcription ◽

Insulin Gene ◽

Insulin Biosynthesis ◽

Insulin Gene Transcription

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Analysis of ∼700 Human Tissue Samples Identifies microRNAs That Are Associated with, Predictive of, and Necessary for Insulin Gene Transcription

Diabetes ◽

10.2337/db18-2160-p ◽

2018 ◽

Vol 67 (Supplement 1) ◽

pp. 2160-P

Author(s):

ANAND HARDIKAR ◽

WILSON WONG ◽

MUGDHA JOGLEKAR ◽

LOUISE T. DALGAARD ◽

ALICIA JENKINS ◽

...

Keyword(s):

Gene Transcription ◽

Human Tissue ◽

Insulin Gene ◽

Tissue Samples ◽

Insulin Gene Transcription

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The Islet β Cell-enriched MafA Activator Is a Key Regulator of Insulin Gene Transcription

Journal of Biological Chemistry ◽

10.1074/jbc.m409475200 ◽

2005 ◽

Vol 280 (12) ◽

pp. 11887-11894 ◽

Cited By ~ 124

Author(s):

Li Zhao ◽

Min Guo ◽

Taka-aki Matsuoka ◽

Derek K. Hagman ◽

Susan D. Parazzoli ◽

...

Keyword(s):

Gene Transcription ◽

Insulin Gene ◽

Β Cell ◽

Insulin Gene Transcription

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Extinction of insulin gene expression in hybrids between beta cells and fibroblasts is accompanied by loss of the putative beta-cell-specific transcription factor IEF1

Molecular and Cellular Biology ◽

10.1128/mcb.11.3.1547-1552.1991 ◽

1991 ◽

Vol 11 (3) ◽

pp. 1547-1552

Author(s):

D Leshkowitz ◽

M D Walker

Keyword(s):

Gene Expression ◽

Dna Binding ◽

Binding Activity ◽

Insulin Gene ◽

Hybrid Cells ◽

Dna Binding Activity ◽

Insulin Producing Cells ◽

Insulin Gene Expression ◽

Insulinoma Cells

Insulin-producing cells and fibroblasts were fused to produce hybrid lines. In hybrids derived from both hamster and rat insulinoma cells, no insulin mRNA could be detected in any of seven lines examined by Northern (RNA) analysis despite the presence in each line of the insulin genes of both parental cells. Hybrid cells were transfected with recombinant chloramphenicol acetyltransferase plasmids containing defined segments of the rat insulin I gene 5' flank. We observed no transcriptional activity of the intact insulin enhancer or of IEB2, a critical cis-acting element of the insulin enhancer. IEB2 has previously been shown to interact in vitro with IEF1, a DNA-binding activity observed selectively in insulin-producing cells. Hybrid cells showed no detectable IEF1 activity. Furthermore, the insulin enhancer was unable to reduce transcription directed by the Moloney sarcoma virus enhancer in a double-enhancer construct. Thus, extinction of insulin gene expression in the hybrids apparently does not operate through a direct action of repressors on the insulin enhancer; rather, extinction is accompanied by, and may be caused by, reduced DNA-binding activity of the putative transcriptional activator IEF1.

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PIASy is a SUMOylation-independent negative regulator of the insulin transactivator MafA

Journal of Molecular Endocrinology ◽

10.1530/jme-19-0172 ◽

2019 ◽

Vol 63 (4) ◽

pp. 297-308

Author(s):

Suzuka Onishi ◽

Kohsuke Kataoka

Keyword(s):

Transcription Factors ◽

Gene Transcription ◽

Gene Promoter ◽

Terminal Region ◽

Insulin Gene ◽

Negative Regulator ◽

Β Cell ◽

E3 Ligases ◽

Amino Terminal ◽

Insulin Gene Transcription

Insulin plays a central role in glucose homeostasis and is produced exclusively by pancreatic islet β-cells. Insulin gene transcription is regulated by a set of β-cell-enriched transcription factors that bind to cis-regulatory elements within the promoter region, and regulation of the insulin gene promoter is closely linked to β-cell functionality. PIASy, a member of the PIAS family of SUMO E3 ligases, is thought to affect insulin gene transcription, but its mechanism of action is not fully understood. Here, we demonstrate that PIASy interacts with MafA and represses insulin gene promoter activity. MafA is a β-cell-restricted basic leucine-zipper transcriptional activator that binds to the C1 element of the insulin gene promoter. In line with previous studies showing the transactivator domain of MafA is SUMOylated, PIASy enhanced the SUMOylation of MafA. However, a SUMOylation-deficient mutant of MafA was still repressed by PIASy, indicating that this modification is dispensable for repression. Using a series of MafA and PIASy mutants, we found that the basic domain of MafA and the amino-terminal region of PIASy containing the SAP domain are necessary for their interaction. In addition, SUMO-interacting motif 1 (SIM1) at the carboxyl-terminal region of PIASy was required to repress the synergistic transactivation of MafA, Pdx1, and Beta2, transcription factors playing central roles in β-cell differentiation and function. The PINIT and SP-RING domains in the middle region of PIASy were dispensable. These findings suggest that PIASy binds to MafA through the SAP domain and negatively regulates the insulin gene promoter through a novel SIM1-dependent mechanism.

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