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

Hussain, Mehboob A.; Miller, Christopher P.; Habener, Joel F.

doi:10.1074/jbc.m107124200

Cited by 55 publications

(33 citation statements)

References 30 publications

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“…Among those enriched in the ␣ cell is brain 4, which is specifically expressed in islet progenitors and differentiating, as well as adult, ␣ cells. It functions as an essential transactivator in glucagon gene expression and possibly as a dominant regulator of ␣ cell lineages (54). This is the HD protein showing the greatest differential in expression, and our data highlight its essential contribution to the ␣ cell's unique development and functional profile.…”

Section: Discussionmentioning

confidence: 85%

Contrasting patterns of expression of transcription factors in pancreatic α and β cells

Wang

Webb

Cao

et al. 2003

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

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Pancreatic ␣ and ␤ cells are derived from the same progenitors but play opposing roles in the control of glucose homeostasis. Disturbances in their function are associated with diabetes mellitus. To identify many of the proteins that define their unique pathways of differentiation and functional features, we have analyzed patterns of gene expression in ␣TC1.6 vs. MIN6 cell lines by using oligonucleotide microarrays. Approximately 9 -10% of >11,000 transcripts examined showed significant differences between the two cell types. Of >700 known transcripts enriched in either cell type, transcription factors and their regulators (TFR) was one of the most significantly different categories. Ninety-six members of the basic zipper, basic helix-loop-helix, homeodomain, zinc finger, high mobility group, and other transcription factor families were enriched in ␣ cells; in contrast, homeodomain proteins accounted for 51% of a total of 45 TFRs enriched in ␤ cells. Our analysis thus highlights fundamental differences in expression of TFR subtypes within these functionally distinct islet cell types. Interestingly, the ␣ cells appear to express a large proportion of factors associated with progenitor or stem-type cells, perhaps reflecting their earlier appearance during pancreatic development. The implications of these findings for a better understanding of ␣ and ␤ cell dysfunction in diabetes mellitus are also considered. P ancreatic islets consist of four endocrine cell types, ␣, ␤, D, and pancreatic peptide (PP). These cell types produce and secrete the major islet hormones: glucagon, insulin, islet amyloid polypeptide (IAPP), somatostatin, and PP, respectively, which regulate fuel and energy homeostasis (1). The ␣ cells secrete glucagon, which stimulates gluconeogenesis and glycogenolysis to prevent hypoglycemia, whereas the ␤ cells increase insulin secretion in response to elevated blood glucose levels. Glucagon and insulin antagonistically regulate the balance of glucose storage, production, and consumption to maintain physiological plasma glucose concentrations. Therefore, the ␣ and ␤ cells together play a central role in glucose homeostasis.Excessive production and secretion of glucagon by the ␣ cells is a common accompaniment to the two main types of diabetes. Physiologically, glucagon secretion is suppressed by hyperglycemia. However, this normal homeostatic suppression is lost in diabetic states, which in turn perpetuates hyperglycemia by stimulating hepatic glucose output (2). Another major typical manifestation of diabetes is an absolute or relative deficiency of insulin from the ␤ cells, resulting in failure to adequately control the blood glucose level (3). Disturbances of ␣ and͞or ␤ cell function thus are central to the failure to maintain physiological glucose levels and related metabolic concomitants of diabetes mellitus.To understand the molecular basis for the development and specialized functions of ␣ and ␤ cells is an important goal for understanding and effectively treating diabetes. Although much effort h...

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Section: Discussionmentioning

confidence: 85%

Contrasting patterns of expression of transcription factors in pancreatic α and β cells

Wang

Webb

Cao

et al. 2003

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

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“…Temporal and spatial expression of HD proteins affecting the commitment of cell lineage in pancreatic islets has been documented. For example, Hussain et al (2002) reported that ectopic misexpression of the POU HD protein Brn-4 by Pdx-1 promoter in transgenic mice resulted in ectopic expression of the glu gene in insulin-expressing pancreatic cells, while misexpressing Brn-4 by rat insulin II promoter did not.…”

Section: Discussionmentioning

confidence: 99%

Role of Cdx-2 in insulin and proglucagon gene expression: a study using the RIN-1056A cell line with an inducible gene expression system

Zhao

Liu²,

Zhang³

et al. 2005

Journal of Endocrinology

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Although the homeobox gene Cdx-2 was initially isolated from the pancreatic cell line HIT-T15, no examination of its role in regulating endogenous insulin gene expression has been reported. To explore further the role of Cdx-2 in regulating both insulin and proglucagon gene expression, we established an ecdysone-inducible Cdx-2 expression system. This report describes a study using the rat insulinoma cell line RIN-1056A, which abundantly expresses both insulin and proglucagon (glu), and relatively high amounts of endogenous Cdx-2. Following the introduction of the inducible Cdx-2 expression system into this cell line and the antibiotic selection procedure, we obtained novel cell lines that displayed dramatically reduced expression of endogenous Cdx-2, in the absence of the inducer. These novel cell lines did not express detectable amounts of glu mRNA or the glucagon hormone, while their insulin expression was not substantially affected. In the presence of the inducer, however, transfected Cdx-2 expression was dramatically increased, accompanied by stimulation of endogenous Cdx-2 expression. More importantly, activated Cdx-2 expression was accompanied by elevated insulin mRNA expression, and insulin synthesis. Cdx-2 bound to the insulin gene promoter enhancer elements, and stimulated the expression of a luciferase reporter gene driven by these enhancer elements. Furthermore, Cdx-2 and insulin gene expressions in the wild-type RIN-1056A cells were stimulated by forskolin treatment, and forskolin-mediated activation on insulin gene expression was attenuated in the absence of Cdx-2. We suggest that Cdx-2 may mediate the second messenger cAMP in regulating insulin gene transcription.

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“…Although transgene expression in pancreatic islets of rodents has been achieved by microinjection of fertilized embryos (24)(25)(26)(27)(28)(29)(30), safe and efficient in vivo targeting of genes to pancreatic islets has been an elusive goal. This paper describes a method for efficient gene delivery to the pancreatic islets, with detection of transgene-encoded proteins (luciferase, human insulin and Cpeptide, hexokinase I) for up to 3 weeks after transfection.…”

Section: Discussionmentioning

confidence: 99%

Efficient gene delivery to pancreatic islets with ultrasonic microbubble destruction technology

Chen

Ding

Bekeredjian³

et al. 2006

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

182

128

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This study describes a method of gene delivery to pancreatic islets of adult, living animals by ultrasound targeted microbubble destruction (UTMD). The technique involves incorporation of plasmids into the phospholipid shell of gas-filled microbubbles, which are then infused into rats and destroyed within the pancreatic microcirculation with ultrasound. Specific delivery of genes to islet beta cells by UTMD was achieved by using a plasmid containing a rat insulin 1 promoter (RIP), and reporter gene expression was regulated appropriately by glucose in animals that received a RIP-luciferase plasmid. To demonstrate biological efficacy, we used UTMD to deliver RIP-human insulin and RIP-hexokinase I plasmids to islets of adult rats. Delivery of the former plasmid resulted in clear increases in circulating human C-peptide and decreased blood glucose levels, whereas delivery of the latter plasmid resulted in a clear increase in hexokinase I protein expression in islets, increased insulin levels in blood, and decreased circulating glucose levels. We conclude that UTMD allows relatively noninvasive delivery of genes to pancreatic islets with an efficiency sufficient to modulate beta cell function in adult animals.diabetes ͉ gene therapy ͉ ultrasound

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

Cited by 55 publications

References 30 publications

Contrasting patterns of expression of transcription factors in pancreatic α and β cells

Contrasting patterns of expression of transcription factors in pancreatic α and β cells

Role of Cdx-2 in insulin and proglucagon gene expression: a study using the RIN-1056A cell line with an inducible gene expression system

Efficient gene delivery to pancreatic islets with ultrasonic microbubble destruction technology

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