Differential regulation of clusterin and its isoforms by androgens in prostate cells.

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Cochrane DR, Wang Z, Muramaki M, Gleave ME, Nelson CC

Differential regulation of clusterin and its isoforms by androgens in prostate cells.

J Biol Chem. 2007 Jan 26;282(4):2278-87. Epub 2006 Dec 4.

PubMed ID

17148459 [ View in PubMed

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Abstract

Clusterin mRNA levels were shown to increase dramatically in rat ventral prostate following castration, and clusterin was therefore originally thought to be repressed by androgens. It was later discovered that the increased clusterin levels are most likely due to castration-induced apoptosis of the prostatic epithelium rather than direct action of the androgen receptor (AR). In the studies presented here, LNCaP cells in culture and rat prostate organ culture were treated with androgens. Clusterin mRNA and protein are shown to increase with androgen treatment in a time- and dose-dependent manner. This induction of clusterin requires AR and can be inhibited by casodex, an AR antagonist. We have found that the first intron of the clusterin gene contains putative androgen response elements. The intronic region is shown to be bound by AR in chromatin immunoprecipitation assays and is transactivated by AR in reporter assays. Two isoforms of clusterin result from alternate transcriptional start sites. Both isoforms are cytoprotective; however, Isoform 1 has the capacity to produce a splice variant that is apoptotic. Real time PCR was used to determine the response of the two isoforms to androgens. Intriguingly, these results illustrated that Isoform 2 was up-regulated, whereas Isoform 1 was down-regulated by androgens. Isoform 2 was also increased as the LNCaP xenograft tumor progressed to androgen-independence, whereas Isoform 1 was unaltered. This androgen regulation of clusterin may underline the cytoprotective role of androgens in normal prostate physiology as well as play an antiapoptotic role in prostate cancer progression.

DrugBank Data that Cites this Article

Polypeptides

Name	UniProt ID
Clusterin	P10909	Details

Pharmaco-transcriptomics

Drug	Drug Groups	Gene	Gene ID	Change	Interaction	Chromosome
Metribolone	Experimental	CLU	1191	downregulated	Metribolone results in decreased expression of CLU mRNA alternative form	8p21.1
Metribolone	Experimental	CLU	1191	upregulated	Metribolone results in increased expression of CLU mRNA	8p21.1
Metribolone	Experimental	CLU	1191	upregulated	Metribolone results in increased expression of CLU mRNA alternative form	8p21.1