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PMID:11486045

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Citation

Iso, T, Sartorelli, V, Poizat, C, Iezzi, S, Wu, HY, Chung, G, Kedes, L and Hamamori, Y (2001) HERP, a novel heterodimer partner of HES/E(spl) in Notch signaling. Mol. Cell. Biol. 21:6080-9

Abstract

HERP1 and -2 are members of a new basic helix-loop-helix (bHLH) protein family closely related to HES/E(spl), the only previously known Notch effector. Like that of HES, HERP mRNA expression is directly up-regulated by Notch ligand binding without de novo protein synthesis. HES and HERP are individually expressed in certain cells, but they are also coexpressed within single cells after Notch stimulation. Here, we show that HERP has intrinsic transcriptional repression activity. Transcriptional repression by HES/E(spl) entails the recruitment of the corepressor TLE/Groucho via a conserved WRPW motif, whereas unexpectedly the corresponding-but modified-tetrapeptide motif in HERP confers marginal repression. Rather, HERP uses its bHLH domain to recruit the mSin3 complex containing histone deacetylase HDAC1 and an additional corepressor, N-CoR, to mediate repression. HES and HERP homodimers bind similar DNA sequences, but with distinct sequence preferences, and they repress transcription from specific DNA binding sites. Importantly, HES and HERP associate with each other in solution and form a stable HES-HERP heterodimer upon DNA binding. HES-HERP heterodimers have both a greater DNA binding activity and a stronger repression activity than do the respective homodimers. Thus, Notch signaling relies on cooperation between HES and HERP, two transcriptional repressors with distinctive repression mechanisms which, either as homo- or as heterodimers, regulate target gene expression.

Links

PubMed PMC87325

Keywords

3T3 Cells; Amino Acid Sequence; Animals; Basic Helix-Loop-Helix Transcription Factors; Binding Sites; COS Cells; Cercopithecus aethiops; DNA/metabolism; Dimerization; Gene Expression Regulation; HeLa Cells; Helix-Loop-Helix Motifs; Histone Deacetylases/metabolism; Homeodomain Proteins/metabolism; Humans; Membrane Proteins/metabolism; Mi-2 Nucleosome Remodeling and Deacetylase Complex; Mice; Molecular Sequence Data; Nuclear Proteins/metabolism; Nuclear Receptor Co-Repressor 1; Proteins; Receptors, Notch; Recombinant Fusion Proteins/genetics; Recombinant Fusion Proteins/metabolism; Repressor Proteins/genetics; Repressor Proteins/metabolism; Signal Transduction; Sin3 Histone Deacetylase and Corepressor Complex; Solutions; Transcription Factors/metabolism; Transcription, Genetic

Significance

Annotations

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

HUMAN:NCOR1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9UBP5

F

Seeded From UniProt

complete

HUMAN:NCOR1

colocalizes_with

GO:0016580: Sin3 complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

RAT:HES1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9QUS4

F

Seeded From UniProt

complete

RAT:HES1

involved_in

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

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:HES1

enables

GO:0043565: sequence-specific DNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:SIN3A

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9UBP5

F

Seeded From UniProt

complete

MOUSE:HEY2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q04666

F

Seeded From UniProt

complete

HUMAN:HEY2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:O75376

F

Seeded From UniProt

complete

HUMAN:HEY2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q60520

F

Seeded From UniProt

complete

HUMAN:HEY2

involved_in

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

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:HEY2

colocalizes_with

GO:0016580: Sin3 complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:HEY2

part_of

GO:0017053: transcription repressor complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:HEY2

enables

GO:0043565: sequence-specific DNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:HEY1

involved_in

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

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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