Differential regulation of clusterin and its isoforms by androgens in prostate cells.
Article Details
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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]
- 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