Pax4 Represses Pancreatic Glucagon Gene Expression

Petersen, Helle V.; Jørgensen, Mette C.; Andersen, Frank G.; Jensen, Jan; F-Nielsen, Tove; Jørgensen, Ragna; Madsen, Ole; Serup, Palle

doi:10.1006/mcbr.2000.0220

Cited by 41 publications

(24 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The silencing of glucagon gene transcription in an a-cell line stably transfected with Pax-4 has been reported recently [24]. In addition, individual Pax-4 positive clones without glucagon gene expression gave rise to solid tumours in rats without modifying plasma glucagon concentrations.…”

Section: Discussionmentioning

confidence: 86%

The pancreatic beta-cell-specific transcription factor Pax-4 inhibits glucagon gene expression through Pax-6

et al. 2002

View full text Add to dashboard Cite

The endocrine pancreas is organised as islets of Langerhans embedded in the exocrine tissue and is composed of four cell types: beta, a, d, and g cells producing insulin, glucagon, somatostatin and the pancreatic polypeptide (PP), respectively. Gene knockout studies have shown the involvement of a variety of transcription factors in pancreas development. Null mutations of the homeodomain proteins pdx-1 and isl-1 result in pancreatic agenesis and the absence of the islets of Langerhans, respectively [1,2]. The lack of Beta2, Pax-6, Pax-4, Nk 2.2, and Nk 6.1 affects the organisation of the endocrine pancreas and the number of endocrine cells or both [3±9]. The formation of specific islet cell types can be affected by the absence of any of these factors: no or few glucagon-producing a cells are observed in homozygous pax-6 mutants, whereas pax-4 knockout mice lack beta and d cells; nk 2.2 and nk 6.1 mu-The pancreatic beta-cell-specific transcription factor Pax-4 inhibits glucagon gene expression through Pax-6 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 a cells, pax-4 homozygous mutant mice lack insulin and somatostatin-producing beta and d cells but contain an increased number of a cells suggesting that a 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 a 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 HNF3a 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 a 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]

show abstract

Section: Discussionmentioning

confidence: 86%

The pancreatic beta-cell-specific transcription factor Pax-4 inhibits glucagon gene expression through Pax-6

et al. 2002

View full text Add to dashboard Cite

show abstract

“…Heterozygous Pax4-knockout mice harbour less mature pancreatic beta and delta cells, but have numerous abnormally clustered alpha cells, indicating the essential role of PAX4 in the differentiation of beta and delta cell lineages [30]. PAX4 has been shown to repress the transcriptional activity of insulin [19] and glucagon [31] promoters. PAX4 is located at 7q32, a region reported to be associated with type 2 diabetes in previous GWAS of Asians [32,33].…”

Section: Discussionmentioning

confidence: 99%

Exome-chip association analysis reveals an Asian-specific missense variant in PAX4 associated with type 2 diabetes in Chinese individuals

Cheung

Tang

et al. 2016

Diabetologia

View full text Add to dashboard Cite

show abstract

“…Transcriptional repressor activities of wild-type PAX4 and PAX4 R192H on insulin and glucagon promoters PAX4 represses transcription activity of both insulin (Shimajiri et al, 2001) and glucagon (Petersen et al, 2000;Ritz-Laser, Estreicher, Gauthier, Mamin, & Edlund, 2002) promoters. We investigated whether or not PAX4 R192H protein would show any defects in these activities.…”

Section: Immunofluorescence Staining Of Wild-type Pax4 and Pax4 R192hmentioning

confidence: 99%

Defective PAX4 R192H transcriptional repressor activities associated with maturity onset diabetes of the young and early onset-age of type 2 diabetes

Kooptiwut

Plengvidhya

Chukijrungroat

et al. 2012

Journal of Diabetes and its Complications

View full text Add to dashboard Cite

Pax4 Represses Pancreatic Glucagon Gene Expression

Cited by 41 publications

References 39 publications

The pancreatic beta-cell-specific transcription factor Pax-4 inhibits glucagon gene expression through Pax-6

The pancreatic beta-cell-specific transcription factor Pax-4 inhibits glucagon gene expression through Pax-6

Exome-chip association analysis reveals an Asian-specific missense variant in PAX4 associated with type 2 diabetes in Chinese individuals

Defective PAX4 R192H transcriptional repressor activities associated with maturity onset diabetes of the young and early onset-age of type 2 diabetes

Contact Info

Product

Resources

About