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PMID:14752053

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Citation

Kim, JY, Chu, K, Kim, HJ, Seong, HA, Park, KC, Sanyal, S, Takeda, J, Ha, H, Shong, M, Tsai, MJ and Choi, HS (2004) Orphan nuclear receptor small heterodimer partner, a novel corepressor for a basic helix-loop-helix transcription factor BETA2/neuroD. Mol. Endocrinol. 18:776-90

Abstract

Small heterodimer partner (SHP; NR0B2) is an atypical orphan nuclear receptor that lacks a conventional DNA binding domain (DBD) and represses the transcriptional activity of various nuclear receptors. In this study, we examined the novel cross talk between SHP and BETA2/NeuroD, a basic helix-loop-helix transcription factor. In vitro and in vivo protein interaction studies showed that SHP physically interacts with BETA2/NeuroD, but not its heterodimer partner E47. Moreover, confocal microscopic study and immunostaining results demonstrated that SHP colocalized with BETA2 in islets of mouse pancreas. SHP inhibited BETA2/NeuroD-dependent transactivation of an E-box reporter, whereas SHP was unable to repress the E47-mediated transactivation and the E-box mutant reporter activity. In addition, SHP repressed the BETA2-dependent activity of glucokinase and cyclin-dependent kinase inhibitor p21 gene promoters. Gel shift and in vitro protein competition assays indicated that SHP inhibits neither dimerization nor DNA binding of BETA2 and E47. Rather, SHP directly repressed BETA2 transcriptional activity and p300-enhanced BETA2/NeuroD transcriptional activity by inhibiting interaction between BETA2 and coactivator p300. We also showed that C-terminal repression domain within SHP is also required for BETA2 repression. However, inhibition of BETA2 activity was not observed by naturally occurring human SHP mutants that cannot interact with BETA2/NeuroD. Taken together, these results suggest that SHP acts as a novel corepressor for basic helix-loop-helix transcription factor BETA2/NeuroD by competing with coactivator p300 for binding to BETA2/NeuroD and by its direct transcriptional repression function.

Links

PubMed Online version:10.1210/me.2003-0311

Keywords

Animals; Basic Helix-Loop-Helix Transcription Factors; COS Cells; DNA-Binding Proteins/metabolism; Dimerization; E1A-Associated p300 Protein; Gene Expression Regulation/physiology; Humans; Mice; Mutation; Nerve Tissue Proteins/metabolism; Nuclear Proteins/metabolism; Protein Structure, Tertiary; Receptors, Cytoplasmic and Nuclear/genetics; Receptors, Cytoplasmic and Nuclear/metabolism; TCF Transcription Factors; Trans-Activators/metabolism; Transcription Factor 7-Like 1 Protein; Transcription Factors/metabolism; Transcriptional Activation

Significance

Annotations

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

HUMAN:TFE2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q09472

F

Seeded From UniProt

complete

HUMAN:TFE2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q13562

F

Seeded From UniProt

complete

HUMAN:TFE2

enables

GO:0001228: DNA-binding transcription activator activity, RNA polymerase II-specific

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:ID2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q15466

F

Seeded From UniProt

complete

HUMAN:EP300

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q13562

F

Seeded From UniProt

complete

HUMAN:EP300

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P15923

F

Seeded From UniProt

complete

HUMAN:NDF1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q09472

F

Seeded From UniProt

complete

HUMAN:NDF1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P15923

F

Seeded From UniProt

complete

HUMAN:NDF1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q15466

F

Seeded From UniProt

complete

HUMAN:NDF1

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:NDF1

involved_in

GO:0051091: positive regulation of DNA-binding transcription factor activity

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:NDF1

enables

GO:0046982: protein heterodimerization activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:NDF1

enables

GO:0070888: E-box binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:NDF1

enables

GO:0001228: DNA-binding transcription activator activity, RNA polymerase II-specific

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:NR0B2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q13562

F

Seeded From UniProt

complete

HUMAN:NR0B2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q02363

F

Seeded From UniProt

complete

HUMAN:NR0B2

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:NR0B2

located_in

GO:0005737: cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:NR0B2

involved_in

GO:0043433: negative regulation of DNA-binding transcription factor activity

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:NR0B2

enables

GO:0003714: transcription corepressor activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:TFE2

enables

GO:0046982: protein heterodimerization activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:TFE2

enables

GO:0003713: transcription coactivator activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:TFE2

enables

GO:0042803: protein homodimerization activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:TFE2

involved_in

GO:0051091: positive regulation of DNA-binding transcription factor activity

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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