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PMID:11875103

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Citation

Norris, JD, Fan, D, Sherk, A and McDonnell, DP (2002) A negative coregulator for the human ER. Mol. Endocrinol. 16:459-68

Abstract

ERalpha is a ligand-activated transcription factor and a key regulator of the processes involved in cellular proliferation and differentiation. In addition, aberrant ERalpha activity is linked to several pathological conditions including breast cancer. A complex network of coregulatory proteins is largely believed to determine the transcriptional activity of ERalpha. We report here the isolation of a protein, denoted RTA for repressor of tamoxifen transcriptional activity, which contains an RNA recognition motif and interacts with the receptor N-terminal activation domain. RTA interacts with RNA in vitro, and its overexpression inhibits the partial agonist activity manifest by the antiestrogen tamoxifen while minimally affecting E2-activated transcription. Mutation of the RNA recognition motif alters RNA binding specificity and results in a dominant negative form of RTA that leads to derepression of ERalpha transcriptional activity, allowing all classes of antiestrogens to manifest partial agonist activity and enhancing agonist efficacy. These findings suggest a role for RNA binding proteins as coregulatory factors of the nuclear receptor family and reveal a novel mechanism by which antiestrogens can manifest agonist activities in some tissues.

Links

PubMed

Keywords

Amino Acid Sequence; Binding Sites; Blotting, Northern; Consensus Sequence; Estradiol/pharmacology; Estrogen Antagonists/pharmacology; Estrogen Receptor alpha; Gene Expression; HeLa Cells; Humans; Molecular Sequence Data; Mutagenesis; RNA/metabolism; RNA-Binding Proteins/chemistry; RNA-Binding Proteins/genetics; RNA-Binding Proteins/physiology; Receptors, Estrogen/drug effects; Receptors, Estrogen/physiology; Repressor Proteins/chemistry; Repressor Proteins/genetics; Repressor Proteins/physiology; Tamoxifen/pharmacology; Tissue Distribution; Transcription, Genetic/drug effects; Transfection; Tumor Cells, Cultured

Significance

Annotations

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

HUMAN:RFOX2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P03372

F

Seeded From UniProt

complete

HUMAN:RFOX2

involved_in

GO:0030520: intracellular estrogen receptor signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:RFOX2

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:RFOX2

involved_in

GO:0016070: RNA metabolic process

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

P

Seeded From UniProt

complete

HUMAN:RFOX2

enables

GO:0003714: transcription corepressor activity

ECO:0000314: direct assay evidence used in manual assertion

F

  • has_input:(UniProtKB:P03372)

Seeded From UniProt

complete

HUMAN:RFOX2

enables

GO:0003723: RNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:RFOX2

enables

GO:0140297: DNA-binding transcription factor binding

ECO:0000314: direct assay evidence used in manual assertion

F

  • has_input:(UniProtKB:P03372)

Seeded From UniProt

complete

HUMAN:RFOX2

involved_in

GO:0045892: negative regulation of transcription, DNA-templated

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:RFOX2

involved_in

GO:0042127: regulation of cell population proliferation

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

P

Seeded From UniProt

complete

HUMAN:ESR1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:O43251

F

Seeded From UniProt

complete

See also

References

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