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PMID:18417529

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Citation

Wang, HW, Muguira, M, Liu, WD, Zhang, T, Chen, C, Aucoin, R, Breslin, MB and Lan, MS (2008) Identification of an INSM1-binding site in the insulin promoter: negative regulation of the insulin gene transcription. J. Endocrinol. 198:29-39

Abstract

In this study, an insulinoma-associated antigen-1 (INSM1)-binding site in the proximal promoter sequence of the insulin gene was identified. The co-transfection of INSM1 with rat insulin I/II promoter-driven reporter genes exhibited a 40-50% inhibitory effect on the reporter activity. Mutational experiments were performed by introducing a substitution, GG to AT, into the INSM1 core binding site of the rat insulin I/II promoters. The mutated insulin promoter exhibited a three- to 20-fold increase in the promoter activity over the wild-type promoter in several insulinoma cell lines. Moreover, INSM1 overexpression exhibited no inhibitory effect on the mutated insulin promoter. Chromatin immunoprecipitation assays using beta TC-1, mouse fetal pancreas, and Ad-INSM1-transduced human islets demonstrated that INSM1 occupies the endogenous insulin promoter sequence containing the INSM1-binding site in vivo. The binding of the INSM1 to the insulin promoter could suppress approximately 50% of insulin message in human islets. The mechanism for transcriptional repression of the insulin gene by INSM1 is mediated through the recruitment of cyclin D1 and histone deacetylase-3 to the insulin promoter. Anti-INSM1 or anti-cyclin D1 morpholino treatment of fetal mouse pancreas enhances the insulin promoter activity. These data strongly support the view that INSM1 is a new zinc-finger transcription factor that modulates insulin gene transcription during early pancreas development.

Links

PubMed PMC2529182 Online version:10.1677/JOE-08-0001

Keywords

Animals; Binding Sites; Cell Line, Tumor; Cyclin D1/physiology; DNA-Binding Proteins/physiology; Gene Expression Regulation; Histone Deacetylases/physiology; Humans; Insulin/genetics; Mice; Pancreas/embryology; Promoter Regions, Genetic; Rats; Repressor Proteins/physiology; Transcription, Genetic

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:HDAC3

part_of

GO:0017053: transcription repressor complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:CCND1

involved_in

GO:0000122: negative regulation of transcription by RNA polymerase II

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:CCND1

part_of

GO:0017053: transcription repressor complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:CCND1

enables

GO:0042826: histone deacetylase binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:O15379

F

Seeded From UniProt

complete

HUMAN:CCND1

enables

GO:0003714: transcription corepressor activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:INSM1

involved_in

GO:0000122: negative regulation of transcription by RNA polymerase II

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:INSM1

part_of

GO:0017053: transcription repressor complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:INSM1

enables

GO:0030332: cyclin binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P24385

F

Seeded From UniProt

complete

HUMAN:INSM1

enables

GO:0031490: chromatin DNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:INSM1

enables

GO:0000978: RNA polymerase II cis-regulatory region sequence-specific DNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:INSM1

enables

GO:0042826: histone deacetylase binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:O15379

F

Seeded From UniProt

complete

HUMAN:INSM1

enables

GO:0003700: DNA-binding transcription factor activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:HDAC3

enables

GO:0003714: transcription corepressor activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:HDAC3

part_of

GO:0017053: transcriptional repressor complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:HDAC3

enables

GO:0030332: cyclin binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P24385

F

Seeded From UniProt

complete

HUMAN:HDAC3

enables

GO:0003682: chromatin binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:HDAC3

involved_in

GO:0000122: negative regulation of transcription by RNA polymerase II

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

Notes

See also

References

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