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PMID:16120611

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Citation

Chen, G, Nomura, M, Morinaga, H, Matsubara, E, Okabe, T, Goto, K, Yanase, T, Zheng, H, Lu, J and Nawata, H (2005) Modulation of androgen receptor transactivation by FoxH1. A newly identified androgen receptor corepressor. J. Biol. Chem. 280:36355-63

Abstract

Androgen signaling plays key roles in the development and progression of prostate cancer, and numerous ongoing studies focus on the regulation of androgen receptor (AR) transactivity to develop novel therapies for the treatment of androgen-independent prostate cancer. FoxH1, a member of the Forkhead-box (FOX) gene family of transcription factors, takes part in mediating transforming growth factor-beta/activin signaling through its interaction with the Smad2.Smad4 complex. Using a series of experiments, we found that FoxH1 repressed both ligand-dependent and -independent transactivation of the AR on androgen-induced promoters. This action of FoxH1 was independent of its transactivation capacity and activin A but relieved by Smad2.Smad4. In addition, the repression of the AR by FoxH1 did not require deacetylase activity. A protein-protein interaction was identified between the AR and FoxH1 independently of dihydrotestosterone. Furthermore, a confocal microscopic analysis of LNCaP cells revealed that the interaction between the AR and FoxH1 occurred in the nucleus and that FoxH1 specifically blocked the foci formation of dihydrotestosterone-activated AR, which has been shown to be correlated with the AR transactivation potential. Taken together, our results indicate that FoxH1 functions as a new corepressor of the AR. Our observations not only strengthen the role of FoxH1 in AR-mediated transactivation but also suggest that therapeutic interventions based on AR-coregulator interactions could be designed to block both androgen-dependent and -independent growth of prostate cancer.

Links

PubMed Online version:10.1074/jbc.M506147200

Keywords

Activins/metabolism; Animals; Blotting, Western; COS Cells; Cell Line, Tumor; Cell Nucleus/metabolism; Cercopithecus aethiops; Dihydrotestosterone/pharmacology; Dose-Response Relationship, Drug; Forkhead Transcription Factors/metabolism; Green Fluorescent Proteins/metabolism; Humans; Image Processing, Computer-Assisted; Immunoprecipitation; Inhibin-beta Subunits/metabolism; Ligands; Male; Microscopy, Confocal; Plasmids/metabolism; Promoter Regions, Genetic; Prostatic Neoplasms/pathology; Protein Binding; RNA/chemistry; Receptors, Androgen/genetics; Receptors, Androgen/metabolism; Repressor Proteins/metabolism; Reverse Transcriptase Polymerase Chain Reaction; Smad2 Protein/metabolism; Smad4 Protein/metabolism; Transcriptional Activation; Transfection; Two-Hybrid System Techniques

Significance

Annotations

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

HUMAN:FOXH1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P10275

F

Seeded From UniProt

complete

HUMAN:FOXH1

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:ANDR

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:O75593

F

Seeded From UniProt

complete

HUMAN:ANDR

enables

GO:0001085: RNA polymerase II transcription factor binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:O75593

F

Seeded From UniProt

complete

HUMAN:FOXH1

part_of

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:FOXH1

involved_in

GO:0033147: negative regulation of intracellular estrogen receptor signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:FOXH1

enables

GO:0050681: androgen receptor binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P10275

F

Seeded From UniProt

complete

HUMAN:FOXH1

involved_in

GO:0060766: negative regulation of androgen receptor signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:FOXH1

enables

GO:0070410: co-SMAD binding

ECO:0000315: mutant phenotype evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:FOXH1

enables

GO:0070412: R-SMAD binding

ECO:0000315: mutant phenotype evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:FOXH1

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

See also

References

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