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PMID:19886863

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Citation

Thomas, MA, Preece, DM and Bentel, JM (2010) Androgen regulation of the prostatic tumour suppressor NKX3.1 is mediated by its 3' untranslated region. Biochem. J. 425:575-83

Abstract

The homeodomain transcription factor NKX3.1 is a prostate-specific tumour suppressor, expression of which is reduced or undetectable in the majority of metastatic prostate tumours. In the normal prostate and in prostate cancer cells, NKX3.1 expression is under tight androgenic control that we have shown to be mediated by its ~2.5 kb 3'UTR (3' untranslated region). Reporter deletion analysis of the NKX3.1 3'UTR identified three regions that were transactivated by DHT (5alpha-dihydrotestosterone) in the AR (androgen receptor)-expressing prostate cancer cell line LNCaP. Reversal of DHT effects by the anti-androgen bicalutamide supported an AR-mediated mechanism, and bioinformatic analysis of the NKX3.1 3'UTR identified canonical AREs (androgen-response elements) in each of the androgen-responsive regions. EMSAs (electrophoretic mobility-shift assays) indicated binding of the AR DNA-binding domain to two of the AREs, a proximal ARE at +2378-2392 from the transcription start site, and a more distal ARE at +3098-3112. ChIP (chromatin immunoprecipitation) analysis provided further evidence of ligand-dependent recruitment of endogenous AR to sequence encompassing each of the two elements, and site-directed mutagenesis and deletion analysis confirmed the contribution of each of the AREs in reporter assays. The present studies have therefore demonstrated that the NKX3.1 3'UTR functions as an androgen-responsive enhancer, with the proximal ARE contributing the majority and the distal ARE providing a smaller, but significant, proportion of the androgen responsiveness of the NKX3.1 3'UTR. Characterization of androgen-responsive regions of the NKX3.1 gene will assist in the identification of transcriptional regulatory mechanisms that lead to the deregulation of NKX3.1 expression in advanced prostate cancers.

Links

PubMed Online version:10.1042/BJ20091109

Keywords

3' Untranslated Regions; Androgens/metabolism; Binding Sites; Cell Line, Tumor; Chromatin Immunoprecipitation; Gene Expression Regulation, Neoplastic; Homeodomain Proteins/genetics; Homeodomain Proteins/metabolism; Humans; Ligands; Male; Mutagenesis, Site-Directed; Plasmids; Prostate/metabolism; Prostatic Neoplasms/metabolism; Transcription Factors/genetics; Transcription Factors/metabolism; Transcriptional Activation

Significance

Annotations

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

HUMAN:ANDR

enables

GO:0000976: transcription cis-regulatory region binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:NKX31

involved_in

GO:2000836: positive regulation of androgen secretion

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:NKX31

enables

GO:0004879: nuclear receptor activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:NKX31

involved_in

GO:0030521: androgen receptor signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:NKX31

involved_in

GO:0071383: cellular response to steroid hormone stimulus

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:ANDR

involved_in

GO:0030521: androgen receptor signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:ANDR

enables

GO:0004879: nuclear receptor activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:ANDR

enables

GO:0044212: transcription regulatory region DNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete


See also

References

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