Repression of insulin gene expression by adenovirus type 5 E1a proteins.

Insulin gene transcription relies on enhancer and promoter elements which are active in pancreatic beta cells. We showed that adenovirus type 5 infection of HIT T-15 cells, a transformed hamster beta cell line, represses insulin gene transcription and mRNA levels. Using expression plasmids transiently introduced into HIT T-15 cells, we showed that adenovirus type 5 E1a transcription regulatory proteins repress insulin enhancer-promoter element activity as assayed with a surrogate xanthine-guanine phosphoribosyltransferase gene. We relate E1a repression of the insulin gene to other examples of repression of enhancer-dependent genes by E1a and discuss the possible relationship of this repression to insulin gene regulation.

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c-jun inhibits transcriptional activation by the insulin enhancer, and the insulin control element is the target of control

Molecular and Cellular Biology ◽

10.1128/mcb.14.1.655-662.1994 ◽

1994 ◽

Vol 14 (1) ◽

pp. 655-662

Author(s):

E Henderson ◽

R Stein

Keyword(s):

Skeletal Muscle ◽

Beta Cells ◽

Gene Transcription ◽

Transcriptional Activation ◽

Pancreatic Beta Cells ◽

Insulin Gene ◽

Control Element ◽

Basic Leucine Zipper ◽

Insulin Control ◽

Insulin Gene Transcription

Selective transcription of the insulin gene in pancreatic beta cells is regulated by its enhancer, located between nucleotides -340 and -91 relative to the transcription start site. One of the principal control elements within the enhancer is found between nucleotides -100 and -91 (GCCATCTGCT, referred to as the insulin control element [ICE]) and is regulated by both positive- and negative-acting transcription factors in the helix-loop-helix (HLH) family. It was previously shown that the c-jun proto-oncogene can repress insulin gene transcription. We have found that c-jun inhibits ICE-stimulated transcription. Inhibition of ICE-directed transcription is mediated by sequences within the carboxy-terminal region of the protein. These c-jun sequences span an activation domain and the basic leucine zipper DNA binding-dimerization region of the protein. Both regions of c-jun are conserved within the other members of the jun family: junB and junD. These proteins also suppress ICE-mediated transcription. The jun proteins do not appear to inhibit insulin gene transcription by binding directly to the ICE. c-jun and junB also block the trans-activation potential of two skeletal muscle-specific HLH proteins, MyoD and myogenin. These results suggests that the jun proteins may be common transcription control factors used in skeletal muscle and pancreatic beta cells to regulate HLH-mediated activity. We discuss the possible significance of these observations to insulin gene transcription in pancreatic beta cells.

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Dominant-negative suppression of HNF-1alpha function results in defective insulin gene transcription and impaired metabolism-secretion coupling in a pancreatic beta -cell line

The EMBO Journal ◽

10.1093/emboj/17.22.6701 ◽

1998 ◽

Vol 17 (22) ◽

pp. 6701-6713 ◽

Cited By ~ 102

Author(s):

H. Wang

Keyword(s):

Beta Cell ◽

Cell Line ◽

Gene Transcription ◽

Pancreatic Beta Cell ◽

Dominant Negative ◽

Insulin Gene ◽

Impaired Metabolism ◽

Beta Cell Line ◽

Insulin Gene Transcription

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c-jun inhibits transcriptional activation by the insulin enhancer, and the insulin control element is the target of control.

Molecular and Cellular Biology ◽

10.1128/mcb.14.1.655 ◽

1994 ◽

Vol 14 (1) ◽

pp. 655-662 ◽

Cited By ~ 24

Author(s):

E Henderson ◽

R Stein

Keyword(s):

Skeletal Muscle ◽

Beta Cells ◽

Gene Transcription ◽

Transcriptional Activation ◽

Pancreatic Beta Cells ◽

Insulin Gene ◽

Control Element ◽

Basic Leucine Zipper ◽

Insulin Control ◽

Insulin Gene Transcription

Selective transcription of the insulin gene in pancreatic beta cells is regulated by its enhancer, located between nucleotides -340 and -91 relative to the transcription start site. One of the principal control elements within the enhancer is found between nucleotides -100 and -91 (GCCATCTGCT, referred to as the insulin control element [ICE]) and is regulated by both positive- and negative-acting transcription factors in the helix-loop-helix (HLH) family. It was previously shown that the c-jun proto-oncogene can repress insulin gene transcription. We have found that c-jun inhibits ICE-stimulated transcription. Inhibition of ICE-directed transcription is mediated by sequences within the carboxy-terminal region of the protein. These c-jun sequences span an activation domain and the basic leucine zipper DNA binding-dimerization region of the protein. Both regions of c-jun are conserved within the other members of the jun family: junB and junD. These proteins also suppress ICE-mediated transcription. The jun proteins do not appear to inhibit insulin gene transcription by binding directly to the ICE. c-jun and junB also block the trans-activation potential of two skeletal muscle-specific HLH proteins, MyoD and myogenin. These results suggests that the jun proteins may be common transcription control factors used in skeletal muscle and pancreatic beta cells to regulate HLH-mediated activity. We discuss the possible significance of these observations to insulin gene transcription in pancreatic beta cells.

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Insulin gene enhancer activity is inhibited by adenovirus 5 E1a gene products

Molecular and Cellular Biology ◽

10.1128/mcb.9.10.4531-4534.1989 ◽

1989 ◽

Vol 9 (10) ◽

pp. 4531-4534

Author(s):

R W Stein ◽

J Whelan

Keyword(s):

Transcription Factors ◽

Gene Transcription ◽

Dna Sequences ◽

Pancreatic Beta Cells ◽

Pancreatic Beta Cell ◽

Insulin Gene ◽

Target Sequence ◽

Flanking Region ◽

Cellular Transcription ◽

Insulin Gene Transcription

Selective transcription of the insulin gene in pancreatic beta cells is regulated by its enhancer, located within the 5'-flanking region of the insulin gene. Transcription from the enhancer is controlled by both positive- and negative-acting cellular transcription factors. It was previously shown that both the 243- and 289-amino-acid adenovirus type 5 E1a proteins can repress insulin gene transcription in vivo. To localize the insulin DNA sequences involved in this response, we examined the effects of a number of mutations within the 5'-flanking region of the rat insulin II gene on E1a-mediated repression of insulin gene transcription. We have found that E1a proteins inhibit enhancer-stimulated transcription of the insulin gene. The enhancer appears to contain at least two genetically separable and independent E1a target sequence elements. Interestingly, these same regions of the insulin enhancer have been shown to be negatively regulated by cellular transcription factors. These results suggest that E1a-like cellular factors may function in the pancreatic beta-cell-specific expression of the insulin gene.

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Insulin gene enhancer activity is inhibited by adenovirus 5 E1a gene products.

Molecular and Cellular Biology ◽

10.1128/mcb.9.10.4531 ◽

1989 ◽

Vol 9 (10) ◽

pp. 4531-4534 ◽

Cited By ~ 13

Author(s):

R W Stein ◽

J Whelan

Keyword(s):

Transcription Factors ◽

Gene Transcription ◽

Dna Sequences ◽

Pancreatic Beta Cells ◽

Pancreatic Beta Cell ◽

Insulin Gene ◽

Target Sequence ◽

Flanking Region ◽

Cellular Transcription ◽

Insulin Gene Transcription

Selective transcription of the insulin gene in pancreatic beta cells is regulated by its enhancer, located within the 5'-flanking region of the insulin gene. Transcription from the enhancer is controlled by both positive- and negative-acting cellular transcription factors. It was previously shown that both the 243- and 289-amino-acid adenovirus type 5 E1a proteins can repress insulin gene transcription in vivo. To localize the insulin DNA sequences involved in this response, we examined the effects of a number of mutations within the 5'-flanking region of the rat insulin II gene on E1a-mediated repression of insulin gene transcription. We have found that E1a proteins inhibit enhancer-stimulated transcription of the insulin gene. The enhancer appears to contain at least two genetically separable and independent E1a target sequence elements. Interestingly, these same regions of the insulin enhancer have been shown to be negatively regulated by cellular transcription factors. These results suggest that E1a-like cellular factors may function in the pancreatic beta-cell-specific expression of the insulin gene.

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