MafA-, NKX2-2-, PAX6-, and PDX1-dependent synthesis of insulin precursor protein

Stable Identifier
R-MMU-186535
Type
Reaction [omitted]
Species
Mus musculus
Compartment
General
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MafA-, NKX2-2-, PAX6-, and PDX1-dependent synthesis of insulin precursor protein

Human and mouse MafA/RIPE3b1 bind to the insulin promoter in vitro, and activate insulin expression via a RIPE3b1-binding element (Olbrot et al. 2002; Matsuoka et al. 2003). In vivo binding of MafA to the endogenous insulin gene was shown by ChIP analysis in murine beta-cell lines (Matsuoka et al. 2003).

Nkx2.2 is essential for the generation of insulin producing cells in mice (Sussel et al. 1998). In vivo binding of NKX2.2 to the endogenous insulin gene was shown by ChIP analysis in murine beta-cell lines (Cissell et al. 2003).

Insulin was markedly reduced in one Pax6 mutant model (Sander et al. 1997), but not in another (St-Onge et al. 1997). Pax6 has been shown to bind the insulin gene in chromatin immunoprecipitation studies (Cissell et al. 2003).

Binding of Pdx1 to the 5'-flanking region of the Insulin gene was observed in vitro (Ohlsson et al. 1993) and in transient transfection studies with rat cell lines (Serup et al. 1996). Reduced activity of Ins1 was reported in mature murine beta cells with targeted disruption of Pdx1 (Ahlgren et al. 1998; Holland et al. 2002). This is consistent with the expression profile from the dominant negative suppression of Pdx1 in rat insulinoma INS1 cell line-derived stable clones (Wang et al. 2001). ChIP experiments confirmed that Pdx1 binds in vivo to the Insulin gene in murine beta cell lines (Chakrabarti et al. 2002).

Literature References
PubMed ID Title Journal Year
12426319 Transcription factor occupancy of the insulin gene in vivo. Evidence for direct regulation by Nkx2.2.

Cissell, MA, Zhao, L, Sussel, L, Henderson, E, Stein, R

J Biol Chem 2003
12011435 Identification of beta-cell-specific insulin gene transcription factor RIPE3b1 as mammalian MafA

Olbrot, M, Rud, J, Moss, LG, Sharma, A

Proc Natl Acad Sci U S A 2002
12368292 MafA is a glucose-regulated and pancreatic beta-cell-specific transcriptional activator for the insulin gene

Kataoka, K, Han, SI, Shioda, S, Hirai, M, Nishizawa, M, Handa, H

J Biol Chem 2002
9163426 Pax6 is required for differentiation of glucagon-producing alpha-cells in mouse pancreas

St-Onge, L, Sosa-Pineda, B, Chowdhury, K, Mansouri, A, Gruss, P

Nature 1997
9224716 Genetic analysis reveals that PAX6 is required for normal transcription of pancreatic hormone genes and islet development

Sander, M, Neubuser, A, Kalamaras, J, Ee, HC, Martin, GR, German, MS

Genes Dev 1997
9637677 beta-cell-specific inactivation of the mouse Ipf1/Pdx1 gene results in loss of the beta-cell phenotype and maturity onset diabetes

Ahlgren, U, Jonsson, J, Jonsson, L, Simu, K, Edlund, H

Genes Dev 1998
9584121 Mice lacking the homeodomain transcription factor Nkx2.2 have diabetes due to arrested differentiation of pancreatic beta cells.

Sussel, L, Kalamaras, J, Hartigan-O'Connor, DJ, Meneses, JJ, Pedersen, RA, Rubenstein, JL, German, MS

Development 1998
12917329 Members of the large Maf transcription family regulate insulin gene transcription in islet beta cells

Matsuoka, TA, Zhao, L, Artner, I, Jarrett, HW, Friedman, D, Means, A, Stein, R

Mol Cell Biol 2003
7901001 IPF1, a homeodomain-containing transactivator of the insulin gene

Ohlsson, H, Karlsson, K, Edlund, T

EMBO J 1993
11825903 Quantitative assessment of gene targeting in vitro and in vivo by the pancreatic transcription factor, Pdx1. Importance of chromatin structure in directing promoter binding.

Chakrabarti, SK, James, JC, Mirmira, RG

J Biol Chem 2002
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