Diabetes and pancreatic tumours in transgenic mice expressing Pa × 6

Yamaoka, Takashi; Yano, Masashi; Yamada, Taketo; Matsushita, Takaya; Moritani, Maki; Yoshimoto, Katsuhiko; Hata, Jun Ichi; Itakura, Mitsuo

doi:10.1007/s001250050051

Cited by 45 publications

(37 citation statements)

References 34 publications

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“…Interestingly, deletion of two Pax2/5/ 8-related genes (egl-38 and pax2) in Caenorhabditis elegans was shown to induce apoptosis in somatic and germline cells via the antiapoptotic gene bcl-2 (Park et al, 2006). Similarly, we have previously demonstrated (Yamaoka et al, 2000). Pax6 could therefore potentially be involved in INS-1E cell proliferation by overriding the effect of Pax4.…”

Section: Discussionsupporting

confidence: 67%

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: Discussionsupporting

confidence: 67%

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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“…However, Pax6 has been shown to be important for the expression of the glucagon, insulin, and somatostatin genes, so it appears that Pax6 may be critical for the development of the endocrine pancreas phenotype development in general. A highly relevant report addresses the phenotypic consequences of the misexpression in transgenic mice of Pax6, a transcription factor important for pancreatic endocrine cell development and differentiation (31). Pax6 was expressed under the control of the insulin and Idx-1 (Pdx-1) promoters.…”

Section: Resultsmentioning

confidence: 99%

Brn-4 Transcription Factor Expression Targeted to the Early Developing Mouse Pancreas Induces Ectopic Glucagon Gene Expression in Insulin-producing β Cells

Hussain

Miller²,

Habener

2002

Journal of Biological Chemistry

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The endocrine pancreas is comprised of ␤ and ␣ cells producing the glucostatic hormones insulin and glucagon, respectively, and arises during development by the differentiation of stem/progenitor cells in the foregut programmed by the ␤ cell lineage-specific homeodomain protein Idx-1. Brain-4 (Brn-4) is expressed in the pancreatic anlaga of the mouse foregut at e10 in the ␣ cells and transactivates glucagon gene expression. We expressed Brn-4 in pancreatic precursors or ␤ cell lineage in transgenic mice by placing it under either Idx-1 or insulin promoter (rat insulin II promoter) control, respectively. Idx-1 expression occurs at developmental day e8.5, and insulin expression occurs at e9.5, respectively. Misexpression of Brn-4 by the Idx-1 promoter results in ectopic expression of the proglucagon gene in insulin-expressing pancreatic ␤ cells, whereas misexpression by rat insulin II promoter did not. The early developmental expression of Brn-4 appears to be a dominant regulator of the glucagon expressing ␣ cell lineage, even in the context of the ␤ cell lineage.The mammalian pancreas develops by the differentiation of endodermal stem/progenitor cells in the foregut of the developing embryo (Refs. 1-3 and references therein). These progenitor cells differentiate into the exocrine acinar cells that produce digestive enzymes and the endocrine islets of Langerhans consisting of the four types of cells specialized for the synthesis of the hormones glucagon (␣ cells), insulin (␤ cells), somatostatin (␦ cells), and pancreatic polypeptide (PP cells). Islet cell-specific differentiation requires the actions of the basic loop helix transcription factors neurogenin-3, ␤2/NeuroD, and the homeodomain proteins Isl-1, Pax4, Pax6, Nkx2.2, Nkx6.6, and Idx-1 (see Refs. 1-4 for review). Idx-1 (Pdx-1/Stf-1/Ipf-1) is transiently expressed in all pancreatic cells as well as in the epithelial layer of the duodenal mucosa during early embryogenesis (5-8). During development, Idx-1 becomes progressively confined to the endocrine ␤ cells where it is critical for the transcriptional regulation of the insulin gene (6, 9). Idx-1 null mice (7), as well as a child homozygous for an inactivating mutation of the Idx-1 (Ipf-1) gene (10), result in a failure of the pancreas to develop (pancreatic agenesis).Brn-4 is a member of the class III family of pou-homeodomain proteins that are highly expressed in neural stem cells and regulate stem cell-specific genes, such as the intermediate filament protein nestin (11, 12). During early pancreas development, the expression of Brn-4 is specifically restricted to stem/progenitor cells that later differentiate into glucagon-producing ␣ cells (13). Brn-4 has not been detected in either differentiating or mature ␤ cells. Brn-4 also stimulates glucagon gene expression by interaction with the ␣ cell-specific G 1 promoter element within the glucagon gene (14).Here we describe that the developmental misexpression of Brn-4 under the control of the mouse Idx-1 promoter (MIP) 1 in mice results in the ectopic expres...

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“…Functional studies have demonstrated that the level of Pax6 protein is important for determining the developmental outcome. Both Pax6 loss of function and gain of function in mice cause ocular abnormalities and defects in the pancreatic islets (16,(28)(29)(30). Thus, the functions of Ey and Dac in IPCs are critically dependent on a defined protein threshold.…”

Section: Discussionmentioning

confidence: 99%

Conserved role for the Dachshund protein with Drosophila Pax6 homolog Eyeless in insulin expression

Okamoto¹,

Nishimori²,

Nishimura³

2012

Proc. Natl. Acad. Sci. U.S.A.

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Members of the insulin family peptides have conserved roles in the regulation of growth and metabolism in a wide variety of metazoans. The Drosophila genome encodes seven insulin-like peptide genes, dilp1-7, and the most prominent dilps (dilp2, dilp3, and dilp5) are expressed in brain neurosecretory cells known as "insulin-producing cells" (IPCs). Although these dilps are expressed in the same cells, the expression of each dilp is regulated independently. However, the molecular mechanisms that regulate the expression of individual dilps in the IPCs remain largely unknown. Here, we show that Dachshund (Dac), which is a highly conserved nuclear protein, is a critical transcription factor that specifically regulates dilp5 expression. Dac was strongly expressed in IPCs throughout development. dac loss-of-function analyses revealed a severely reduced dilp5 expression level in young larvae. Dac interacted physically with the Drosophila Pax6 homolog Eyeless (Ey), and these proteins synergistically promoted dilp5 expression. In addition, the mammalian homolog of Dac, Dach1/2, facilitated the promoting action of Pax6 on the expression of islet hormone genes in cultured mammalian cells. These observations indicate the conserved role of Dac/Dach in controlling insulin expression in conjunction with Ey/Pax6.

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Diabetes and pancreatic tumours in transgenic mice expressing Pa × 6

Cited by 45 publications

References 34 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

Brn-4 Transcription Factor Expression Targeted to the Early Developing Mouse Pancreas Induces Ectopic Glucagon Gene Expression in Insulin-producing β Cells

Conserved role for the Dachshund protein with Drosophila Pax6 homolog Eyeless in insulin expression

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