[beta ]-cell dysfunction in late-onset diabetic subjects carrying homozygous mutation in transcription factors NeuroD1 and Pax4

Kanatsuka, Azuma; Tokuyama, Yoshiharu; Nozaki, Osamu; Matsui, Kana; Egashira, Tohru

doi:10.1053/meta.2002.34707

Cited by 39 publications

(29 citation statements)

References 26 publications

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“…Several studies in the Japanese population and one in Afro-Americans have associated mutations in the pax4 gene to type II diabetes, whereas polymorphisms have been linked to type I diabetes in Scandinavian, German and Swiss families (Shimajiri et al, 2001(Shimajiri et al, , 2003Kanatsuka et al, 2002;Holm et al, 2004;MauvaisJarvis et al, 2004;Biason-Lauber et al, 2005;Tokuyama et al, 2006). These genetic studies suggest an important role of this factor in regulating b-cell function and/or mass in adult islets.…”

Section: Introductionmentioning

confidence: 99%

The transcription factor PAX4 acts as a survival gene in INS-1E insulinoma cells

Brun¹,

Duhamel²,

He³

et al. 2007

Oncogene

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The paired/homeodomain transcription factor Pax4 is essential for islet b-cell generation during pancreas development and their survival in adulthood. High Pax4 expression was reported in human insulinomas indicating that deregulation of the gene may be associated with tumorigenesis. We report that rat insulinoma INS-1E cells express 25-fold higher Pax4 mRNA levels than rat islets. In contrast to primary b-cells, activin A but not betacellulin or glucose induced Pax4 mRNA levels indicating dissociation of Pax4 expression from insulinoma cell proliferation. Short hairpin RNA adenoviral constructs targeted to the paired domain or homeodomain (viPax4PD and viPax4HD) were generated. Pax4 mRNA levels were lowered by 73 and 50% in cells expressing either viPax4PD or viPax4HD. Transcript levels of the Pax4 target gene bcl-xl were reduced by 53 and 47%, whereas Pax6 and Pdx1 mRNA levels were unchanged. viPax4PD-infected cells displayed a twofold increase in spontaneous apoptosis and were more susceptible to cytokine-induced cell death. In contrast, proliferation was unaltered. RNA interference-mediated repression of insulin had no adverse effects on either Pax4 or Pdx1 expression as well as on cell replication or apoptosis. These results indicate that Pax4 is redundant for proliferation of insulinoma cells, whereas it is essential for survival through upregulation of the antiapoptotic gene bcl-xl.

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Section: Introductionmentioning

confidence: 99%

The transcription factor PAX4 acts as a survival gene in INS-1E insulinoma cells

Brun¹,

Duhamel²,

He³

et al. 2007

Oncogene

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“…The mutant protein exhibited loss of function relative to the wild type and seemed to be associated with type 2 diabetes. Another study from Japan reported that this mutant was associated with late-onset type 2 diabetes and was correlated with impaired first-phase insulin secretion [4].…”

mentioning

confidence: 99%

To: Biason-Lauber A, Boehm B, Lang-Muritano M et al. (2005) Association of childhood type 1 diabetes mellitus with a variant of PAX4: possible link to beta cell regenerative capacity. Diabetologia 48:900–905

et al. 2005

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“…The mutant allele occurred at a low frequency (2.0%) within this population [6], and Kanatsuka and coworkers described the same PAX4 mutation in patients with late-onset type 2 diabetes [7]. Interestingly, this mutation was associated with impaired first-phase insulin secretion, providing further evidence for the involvement of PAX4 in beta cell function [7]. However, it is not clear from these studies whether the R121W PAX4 missense mutation, whose functional effects have not been demonstrated in insulinproducing cells, may affect beta cell mass in these patients.…”

mentioning

confidence: 69%

“…A recent study reported a linkage between a homozygous missense mutation (R121W) in PAX4 and type 2 diabetes in a Japanese population [6]. The mutant allele occurred at a low frequency (2.0%) within this population [6], and Kanatsuka and coworkers described the same PAX4 mutation in patients with late-onset type 2 diabetes [7]. Interestingly, this mutation was associated with impaired first-phase insulin secretion, providing further evidence for the involvement of PAX4 in beta cell function [7].…”

mentioning

confidence: 93%

Beta cell regeneration meets autoimmunity: PAX4 variants in type 1 diabetes

Tiedge

2005

Diabetologia

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Type 1 diabetes may be considered as a disease that results from an imbalance between selective autoimmune destruction of pancreatic beta cells and beta cell regeneration. This gives rise to an intriguing question: is impaired beta cell regeneration in itself an important determinant of susceptibility to type 1 diabetes [1,2]? Two lines of investigation have recently-and more or less independently-investigated the mechanisms that underlie beta cell development and regeneration, and the mechanisms involved in beta cell destruction by immune cells and proinflammatory cytokines. In this issue of Diabetologia, Biason-Lauber and coworkers provide evidence that a genomic variant of PAX4 is linked to the development of type 1 diabetes [3].PAX4 is a member of the Pax family of homeodomain transcription factors that are operative during the development of the endocrine pancreas and have been shown to be essential for beta cell development and beta cell function [4]. In mice, this transcription factor is expressed on or around Day 9 in cells of the dorsal pancreatic rudiment, with peak expression occurring between Day 13 and 15, followed by a decline until birth. PAX4 has been identified as a downstream target of neurogenin 3, another important transcription factor for the development of the endocrine pancreas [4]. Studies on pax4 knock-out mice showed a profound reduction in beta cell mass and a severe diabetic syndrome after birth. Atypically clustered alpha cells and ghrelin-positive cells were detected in the pancreas, and it was concluded that PAX4 suppresses the development of these cell types [4].The pivotal role played by PAX4 in beta cell development and function has prompted genetic linkage analyses of this gene in cohorts of diabetic patients, with particular focus on type 2 diabetes. These studies yielded conflicting results. Screening of French MODY families showed no linkage between type 2 diabetes and markers of PAX4 [5]. Although the P321H missense mutation was not associated with MODY diabetes, it does seem to be linked to susceptibility to type 1 diabetes, as discussed below. A recent study reported a linkage between a homozygous missense mutation (R121W) in PAX4 and type 2 diabetes in a Japanese population [6]. The mutant allele occurred at a low frequency (2.0%) within this population [6], and Kanatsuka and coworkers described the same PAX4 mutation in patients with late-onset type 2 diabetes [7]. Interestingly, this mutation was associated with impaired first-phase insulin secretion, providing further evidence for the involvement of PAX4 in beta cell function [7]. However, it is not clear from these studies whether the R121W PAX4 missense mutation, whose functional effects have not been demonstrated in insulinproducing cells, may affect beta cell mass in these patients.What is the situation in type 1 diabetes? Through microsatellite analysis of Scandinavian multiplex families, Holm and co-workers demonstrated a linkage between type 1 diabetes and a region on chromosome 7 (7q32) that carries PAX4, but ...

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[beta ]-cell dysfunction in late-onset diabetic subjects carrying homozygous mutation in transcription factors NeuroD1 and Pax4

Cited by 39 publications

References 26 publications

The transcription factor PAX4 acts as a survival gene in INS-1E insulinoma cells

The transcription factor PAX4 acts as a survival gene in INS-1E insulinoma cells

To: Biason-Lauber A, Boehm B, Lang-Muritano M et al. (2005) Association of childhood type 1 diabetes mellitus with a variant of PAX4: possible link to beta cell regenerative capacity. Diabetologia 48:900–905

Beta cell regeneration meets autoimmunity: PAX4 variants in type 1 diabetes

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