Abstract.
Aims/hypothesis:
The paired-homeobox genes pax-4 and pax-6 are crucial for islet development; whereas the null mutation of pax-6 results in the nearly absence of glucagon-producing α cells, pax-4 homozygous mutant mice lack insulin and somatostatin-producing beta and δ cells but contain an increased number of α cells suggesting that α cells could develop by a default mechanism.
Methods:
To investigate whether beta-cell specific factors act negatively on glucagon gene transcription, we ectopically expressed pax-4 in glucagon producing InR1G9 cells; Pax-4 inhibited basal transcription of the glucagon gene promoter by 60 %. To assess the mechanism of this inhibition, we cotransfected the non-islet cell line BHK-21 with Pax-4 and various transcription factors present in α cells.
Results:
In addition to a general repressor activity on basal glucagon gene promoter activity of 30–50 %, a specific 90 % inhibition of Pax-6 mediated transactivation was observed. In contrast, Pax-4 had no effect on Cdx-2/3 or HNF3α mediated transcriptional activation. Pax-4 showed similar affinity to the Pax-6 binding sites on the glucagon gene promoter compared to Pax-6, but varying with KCl concentrations.
Conclusion/interpretation:
Pax-4 impairs glucagon gene transcription specifically through inhibition of Pax-6 mediated transactivation. Transcriptional inhibition seems to be mediated by direct DNA binding competition with Pax-6 and potentially additional mechanisms such as protein-protein interactions and a general repressor activity of Pax-4. Glucagon gene expression in α cells could thus result from both the presence of islet cell specific transcription factors and the absence of Pax-4. [Diabetologia (2002) 45: 97–107]
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
Author information
Authors and Affiliations
Additional information
Received: 4 July 2001 and in revised form: 12 September 2001
Rights and permissions
About this article
Cite this article
Ritz-Laser, B., Estreicher, A., Gauthier, B. et al. The pancreatic beta-cell-specific transcription factor Pax-4 inhibits glucagon gene expression through Pax-6. Diabetologia 45, 97–107 (2002). https://doi.org/10.1007/s125-002-8249-9
Issue Date:
DOI: https://doi.org/10.1007/s125-002-8249-9