Synergistic activation of the insulin gene by a LIM-homeo domain protein and a basic helix-loop-helix protein: building a functional insulin minienhancer complex.

German, Michael S.; Wang, Juehu; Chadwick, Robert B.; Rutter, William J.

doi:10.1101/gad.6.11.2165

Cited by 389 publications

(310 citation statements)

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“…4B). Co-transfection of C/EBP␤ and Ϫ410INS-LUC into BHK21 cells (a baby hamster kidney cell line that was used to characterize the effects of the homeodomain proteins Lmx-1 and Cdx-3 on rat insulin I gene transcription (54)) confirmed the findings of the HeLa cell transfection experiments (data not shown). These data suggest that C/EBP␤ is a positive regulatory factor for the rat insulin I gene in non-␤-cells.…”

Section: Potential C/ebp␤-binding Sites In the Promoters Of The Rat Asupporting

confidence: 66%

“…The E2A gene products, E12, E47, and/or E2-5, bind to the Far and Nir boxes and activate the rat insulin I gene promoter synergistically with the homeodomain proteins IDX-1 (IPF-1/STF-1/ PDX-1), HNF-1␣, and Lmx-1 (52,54,60), which bind to the FLAT and P1 elements. Although C/EBP␤ activates the rat insulin I gene promoter in non-␤-cells through binding to the newly identified CEB box, this interaction does not mediate the repression of the rat insulin I promoter by C/EBP␤ in ␤-cells.…”

Section: Discussionmentioning

confidence: 99%

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Pancreatic β-Cell-specific Repression of Insulin Gene Transcription by CCAAT/Enhancer-binding Protein β

Lu¹,

Seufert²,

Habener

1997

Journal of Biological Chemistry

120

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Chronic exposure of ␤-cells to supraphysiologic glucose concentrations results in decreased insulin gene transcription. Here we identify the basic leucine zipper transcription factor, CCAAT/enhancer-binding protein ␤ (C/EBP␤), as a repressor of insulin gene transcription in conditions of supraphysiological glucose levels. C/EBP␤ is expressed in primary rat islets. Moreover, after exposure to high glucose concentrations the ␤-cell lines HIT-T15 and INS-1 express increased levels of C/ EBP␤. The rat insulin I gene promoter contains a consensus binding motif for C/EBP␤ (CEB box) that binds C/EBP␤. In non-␤-cells C/EBP␤ stimulates the activity of the rat insulin I gene promoter through the CEB box. Paradoxically, in ␤-cells C/EBP␤ inhibits transcription, directed by the promoter of the rat insulin I gene by direct protein-protein interaction with a heptad leucine repeat sequence within activation domain 2 of the basic helix-loop-helix transcription factor E47. This interaction leads to the inhibition of both dimerization and DNA binding of E47 to the E-elements of the insulin promoter, thereby reducing functionally the transactivation potential of E47 on insulin gene transcription. We suggest that the induction of C/EBP␤ in pancreatic ␤-cells by chronically elevated glucose levels may contribute to the impaired insulin secretion in severe type II diabetes mellitus.Insulin is a hormone essential for the control of mammalian glucose homeostasis and is produced predominantly in pancreatic ␤-cells of adult animals (1). The expression of the insulin gene occurs to a large extent at the level of transcription. Control elements residing in the 5Ј 350-base pair sequence flanking exon 1 of the rat insulin I gene are sufficient to direct ␤-cell-specific expression (2) (Fig. 1A). Arrays of A and E elements 1 (Far-FLAT, Nir-P1) constitute symmetrical enhansons that cooperatively account for Ͼ90% of the transcriptional activity of the insulin gene promoter (3). The E elements are recognition motifs for transcription factors in the basic helixloop-helix (bHLH) 2 family, such as E12 and E47, which activate the insulin promoter in close synergism with A element binding homeobox transcription factors, such as IDX-1.Chronic hyperglycemia may contribute to the pancreatic ␤-cell dysfunction observed in patients with type II diabetes, a phenomenon attributed to the concept of glucose toxicity (4). Studies using in vivo animal models and in vitro ␤-cell lines have demonstrated that a reduction of insulin gene transcription by glucose toxicity is associated with the loss of transactivator proteins such as IDX-1/IPF-1/STF-1 and RIPE3b1-binding protein (5-10). Because insulin gene transcription is both positively and negatively regulated, we sought to identify repressors that might also mediate the effects of glucose toxicity on insulin gene transcription. In this report we describe CCAAT/enhancer binding protein-␤ (C/EBP␤) as a glucoseinduced repressor of insulin gene transcription.C/EBPs are a family of transcription factors that regulate...

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Section: Potential C/ebp␤-binding Sites In the Promoters Of The Rat Asupporting

confidence: 66%

Section: Discussionmentioning

confidence: 99%

Pancreatic β-Cell-specific Repression of Insulin Gene Transcription by CCAAT/Enhancer-binding Protein β

Lu¹,

Seufert²,

Habener

1997

Journal of Biological Chemistry

120

View full text Add to dashboard Cite

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“…Other important elements are known as E1 and A3 [40][41][42][43][44][45]. The pancreatic islet restricted transcription factors BETA2/NeuroD and PDX1, which bind to the E1 and A3 elements, have been isolated.…”

Section: Discussionmentioning

confidence: 99%

Mouse MafA, homologue of zebrafish somite Maf 1, contributes to the specific transcriptional activity through the insulin promoter

Kajihara

Sone

Amemiya

et al. 2003

Biochemical and Biophysical Research Communications

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Large Maf transcription factors, which are members of the basic leucine zipper (b-Zip) superfamily, have been reported to be involved in embryonic development and cell differentiation. Previously, we isolated a novel zebrafish large Maf cDNA, somite Maf1 (SMaf1), which possesses transactivational activity within its N-terminus domain. To elucidate SMaf1 function in mammals, we tried to isolate the mouse homologue of zebrafish SMaf1. We isolated the mouse homologue of zebrafish SMaf1, which is the same molecule as the recently reported MafA. MafA mRNA was detected in formed somites, head neural tube, and liver cells in the embryos. In the adult mouse, MafA transcript was amplified in the brain, lung, spleen, and kidney by RT-PCR. MafA mRNA was also detectable in b-cell line. Next, we analyzed the transcriptional activity of MafA using rat insulin promoters I and II (RIPI and II), since a part of RIP sequence was similar to the Maf recognition element (MARE) and MafA was expressed in pancreatic b-cells. MafA was able to activate transcription from RIPII, but not RIPI, in a dose dependent manner and the activity was dependent on RIPE3b/C1 sequences. In addition, the amount of MafA protein was regulated by glucose concentration. These results indicate that MafA is the homologue of zebrafish SMaf1 and acts as a transcriptional activator of the insulin gene promoter through the RIPE3b element.

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“…The ubiquitous E12/E47, ITF-2, and USF proteins have been implicated in combinatorial control with other proteins, including cell-specific factors. The E12/E47 and ITF-2 proteins have been shown to functionally interact with homeodomain proteins to help direct cell-specific gene expression (22)(23)(24). The USF proteins were initially identified as upstream stimulatory factors that control the adenovirus major late promoter (25)(26)(27).…”

mentioning

confidence: 99%

Binding of Upstream Stimulatory Factor and a Cell-specific Activator to the Calcitonin/Calcitonin Gene-related Peptide Enhancer

Lanigan

Russo

1997

Journal of Biological Chemistry

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The calcitonin/calcitonin gene-related peptide (CT/ CGRP) gene is selectively transcribed in thyroid C cells and neurons. We have previously shown that the rat CT/CGRP cell-specific enhancer is synergistically regulated by a helix-loop-helix (HLH) protein and the OB2 octamer-binding protein. In this report, we show that the HLH-OB2 enhancer is required for full promoter activity, even in the context of other HLH elements.Since this enhancer appears to be a major controlling element, we have characterized the HLH and OB2 DNA binding proteins. We have identified the major HLH complex as a heterodimer of the ubiquitous upstream stimulatory factor (USF)-1 and USF-2 proteins. USF bound the enhancer with a reasonably high affinity (K D 1.6 nM), comparable to other genes. Characterization of a series of mutations revealed that a portion of the HLH motif is also recognized by OB2 and confirmed that HLH activity requires OB2. We have shown that OB2 is a single DNA binding protein based on UV cross-linking studies. The 68-kDa protein-DNA complex was detected only in C cell lines, including a human C cell line that has robust HLH-OB2 enhancer activity. These results suggest that the calcitonin/CGRP gene is controlled by the combinatorial activity of a ubiquitous USF HLH heterodimer and an associated cell-specific activator.

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Synergistic activation of the insulin gene by a LIM-homeo domain protein and a basic helix-loop-helix protein: building a functional insulin minienhancer complex.

Cited by 389 publications

References 50 publications

Pancreatic β-Cell-specific Repression of Insulin Gene Transcription by CCAAT/Enhancer-binding Protein β

Pancreatic β-Cell-specific Repression of Insulin Gene Transcription by CCAAT/Enhancer-binding Protein β

Mouse MafA, homologue of zebrafish somite Maf 1, contributes to the specific transcriptional activity through the insulin promoter

Binding of Upstream Stimulatory Factor and a Cell-specific Activator to the Calcitonin/Calcitonin Gene-related Peptide Enhancer

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