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PMID:17938205

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Citation

Dillon, RL, Brown, ST, Ling, C, Shioda, T and Muller, WJ (2007) An EGR2/CITED1 transcription factor complex and the 14-3-3sigma tumor suppressor are involved in regulating ErbB2 expression in a transgenic-mouse model of human breast cancer. Mol. Cell. Biol. 27:8648-57

Abstract

Amplification and elevated expression of the ErbB2 receptor tyrosine kinase occurs in 20% of human breast cancers and is associated with a poor prognosis. We have previously demonstrated that mammary tissue-specific expression of activated ErbB2 under the control of its endogenous promoter results in mammary tumor formation. Tumor development was associated with amplification and overexpression of ErbB2 at both the transcript and protein levels. Here we demonstrate that the EGR2/Krox20 transcription factor and its coactivator CITED1 are coordinately upregulated during ErbB2 tumor induction. We have identified an EGR2 binding site in the erbB2 promoter and demonstrated by chromatin immunoprecipitation assays that EGR2 and CITED1 associate specifically with this region of the promoter. EGR2 and CITED1 were shown to associate, and expression from an erbB2 promoter-reporter construct was stimulated by EGR2 and was further enhanced by CITED1 coexpression. Furthermore, expression of the 14-3-3sigma tumor suppressor led to downregulation of ErbB2 protein levels and relocalization of EGR2 from the nucleus to the cytoplasm. Taken together, these observations suggest that, in addition to an increased gene copy number and upregulation of EGR2 and CITED1, an elevated erbB2 transcript level involves the loss of 14-3-3sigma, which sequesters a key transcriptional regulator of the erbB2 promoter.

Links

PubMed PMC2169423 Online version:10.1128/MCB.00866-07

Keywords

14-3-3 Proteins/metabolism; Animals; Breast Neoplasms/genetics; Breast Neoplasms/pathology; Cell Line; Disease Models, Animal; Early Growth Response Protein 2/genetics; Early Growth Response Protein 2/metabolism; Female; Gene Expression Regulation, Neoplastic; Humans; Integrases/metabolism; Mammary Tumor Virus, Mouse; Mice; Mice, Transgenic; Nuclear Proteins/genetics; Nuclear Proteins/metabolism; Promoter Regions, Genetic/genetics; Protein Binding; Protein Transport; Receptor, erbB-2/genetics; Receptor, erbB-2/metabolism; Subcellular Fractions/metabolism; Trans-Activators/genetics; Trans-Activators/metabolism; Transcriptional Activation/genetics; Up-Regulation

Significance

Annotations

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

MOUSE:1433S

involved_in

GO:0046827: positive regulation of protein export from nucleus

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:1433S

enables

GO:0051219: phosphoprotein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P08152

F

Seeded From UniProt

complete

MOUSE:EGR2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:O70456

F

Seeded From UniProt

complete

MOUSE:EGR2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P97769

F

Seeded From UniProt

complete

MOUSE:EGR2

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:EGR2

located_in

GO:0005737: cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:EGR2

involved_in

GO:0006611: protein export from nucleus

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:EGR2

enables

GO:0003682: chromatin binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:EGR2

enables

GO:0003700: DNA-binding transcription factor activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:EGR2

involved_in

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

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:EGR2

enables

GO:0000976: transcription cis-regulatory region binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:CITE1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P08152

F

Seeded From UniProt

complete

MOUSE:CITE1

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:CITE1

enables

GO:0003682: chromatin binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:CITE1

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:CITE1

involved_in

GO:0043627: response to estrogen

ECO:0000304: author statement supported by traceable reference used in manual assertion

P

Seeded From UniProt

complete


See also

References

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