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PMID:20228809

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Citation

Drost, J, Mantovani, F, Tocco, F, Elkon, R, Comel, A, Holstege, H, Kerkhoven, R, Jonkers, J, Voorhoeve, PM, Agami, R and Del Sal, G (2010) BRD7 is a candidate tumour suppressor gene required for p53 function. Nat. Cell Biol. 12:380-9

Abstract

Oncogene-induced senescence is a p53-dependent defence mechanism against uncontrolled proliferation. Consequently, many human tumours harbour p53 mutations and others show a dysfunctional p53 pathway, frequently by unknown mechanisms. Here we identify BRD7 (bromodomain-containing 7) as a protein whose inhibition allows full neoplastic transformation in the presence of wild-type p53. In human breast tumours harbouring wild-type, but not mutant, p53 the BRD7 gene locus was frequently deleted and low BRD7 expression was found in a subgroup of tumours. Functionally, BRD7 is required for efficient p53-mediated transcription of a subset of target genes. BRD7 interacts with p53 and p300 and is recruited to target gene promoters, affecting histone acetylation, p53 acetylation and promoter activity. Thus, BRD7 suppresses tumorigenicity by serving as a p53 cofactor required for the efficient induction of p53-dependent oncogene-induced senescence.

Links

PubMed Online version:10.1038/ncb2038

Keywords

Acetylation; Binding Sites; Breast Neoplasms/genetics; Breast Neoplasms/metabolism; Breast Neoplasms/pathology; Cell Aging/genetics; Cell Line, Tumor; Cell Proliferation; Cell Transformation, Neoplastic/genetics; Cell Transformation, Neoplastic/metabolism; Chromosomal Proteins, Non-Histone/genetics; Chromosomal Proteins, Non-Histone/metabolism; Female; Gene Expression Regulation, Neoplastic; Genes, Tumor Suppressor; Genes, ras; Histones/metabolism; Humans; Mutation; Promoter Regions, Genetic; Protein Binding; RNA Interference; Recombinant Fusion Proteins/metabolism; Time Factors; Transcription, Genetic; Tumor Suppressor Protein p53/genetics; Tumor Suppressor Protein p53/metabolism; p300-CBP Transcription Factors/metabolism

Significance

Annotations

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

HUMAN:P53

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9NPI1

F

Seeded From UniProt

complete

HUMAN:P53

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9NPI1

F

Seeded From UniProt

complete

HUMAN:EP300

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9NPI1

F

Seeded From UniProt

complete

HUMAN:BRD7

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q09472

F

Seeded From UniProt

complete

HUMAN:BRD7

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:BRD7

involved_in

GO:0008285: negative regulation of cell population proliferation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:BRD7

enables

GO:0002039: p53 binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P04637

F

Seeded From UniProt

complete

HUMAN:BRD7

enables

GO:0003713: transcription coactivator activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:BRD7

involved_in

GO:0045893: positive regulation of transcription, DNA-templated

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:BRD7

involved_in

GO:0035066: positive regulation of histone acetylation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:BRD7

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P04637

F

Seeded From UniProt

complete

HUMAN:BRD7

enables

GO:0000976: transcription cis-regulatory region binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:EP300

enables

GO:0016407: acetyltransferase activity

ECO:0000269: experimental evidence used in manual assertion

F

Seeded From UniProt

complete


See also

References

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