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Increase in PDX-1 levels suppresses insulin gene expression in RIN 1046-38 cells.
R Seijffers1, O Ben-David, Y Cohen
1Endocrine Institute, Sheba Medical Center, Tel-Hashomer, Israel.
Endocrinology
|June 29, 1999
Summary
Insulin production declines in aged cells due to altered transcription factor levels. Pancreatic and duodenal homeobox protein 1 (PDX-1) acts as both an activator and repressor of insulin gene expression, depending on its cellular concentration.
Area of Science:
- Cell Biology
- Molecular Biology
- Endocrinology
Background:
- RIN1046-38 cells show reduced insulin secretion and content with increasing passage number.
- The underlying mechanisms for decreased insulin production in aged cell cultures require elucidation.
Purpose of the Study:
- To investigate the role of insulin promoter activity and transcription factors in passage-dependent insulin reduction.
- To determine the dual role of PDX-1 as an activator or repressor in insulin gene expression.
Main Methods:
- Analysis of insulin promoter activity and nuclear factor levels (E47, BETA2, PDX-1) in aged RIN-38 cells.
- Overexpression of PDX-1 using recombinant adenovirus technology in RIN-38 and HIT-T15 cells.
Main Results:
- Decreased insulin secretion correlated with reduced promoter activity and lower E47/BETA2 levels, but paradoxically higher PDX-1.
- PDX-1 overexpression suppressed insulin promoter activity in RIN-38 cells.
- PDX-1 demonstrated dose-dependent regulation of insulin promoter activity in HIT-T15 cells, acting as an activator at low doses and a repressor at high doses.
Conclusions:
- PDX-1's role in insulin gene transcription is dose-dependent.
- Both low and high nuclear PDX-1 levels, influenced by cooperating transcription factors, can impair insulin production.