HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 282, Issue 4, 2278-2287, January 26, 2007

This Article Full Text Full Text (PDF) All Versions of this Article: 282/4/2278    most recent M608162200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Cochrane, D. R. Articles by Nelson, C. C. Search for Related Content PubMed PubMed Citation Articles by Cochrane, D. R. Articles by Nelson, C. C. Social Bookmarking                      What's this?

Differential Regulation of Clusterin and Its Isoforms by Androgens in Prostate Cells^*

Dawn R. Cochrane^¶1, Zhou Wang^||, Motosugu Muramaki^¶, Martin E. Gleave^¶, and Colleen C. Nelson^¶2

From the Department of Genetics, Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada, ^¶The Prostate Centre, Vancouver General Hospital, Vancouver V6H 3Z6, Canada, and the ^||Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15232

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.

Received for publication, August 24, 2006 , and in revised form, November 9, 2006.

^* This work was supported by NCIC Program Grant 102003. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Senior Scholar of the Michael Smith Foundation for Health Research.

² Supported by Scholarship funds from the Michael Smith Foundation for Health Research, Canadian Institutes of Health Research, and the Canadian Prostate Cancer Research Initiative. To whom correspondence should be addressed: Prostate Centre at VGH, 2660 Oak St., Vancouver, British Columbia V6H 3Z6, Canada. Tel.: 604-875-5555 (ext. 64282); Fax: 604-875-5654; E-mail: colleen.nelson{at}ubc.ca.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?