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

J. Biol. Chem., Vol. 283, Issue 30, 20989-21001, July 25, 2008

This Article Full Text Full Text (PDF) All Versions of this Article: 283/30/20989    most recent M802392200v1 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 HighWire Citing Articles via Google Scholar Google Scholar Articles by Ponguta, L. A. Articles by Wilson, E. M. Search for Related Content PubMed PubMed Citation Articles by Ponguta, L. A. Articles by Wilson, E. M. Social Bookmarking                      What's this?

Site-specific Androgen Receptor Serine Phosphorylation Linked to Epidermal Growth Factor-dependent Growth of Castration-recurrent Prostate Cancer^*

Liliana A. Ponguta^¶, Christopher W. Gregory^¶1, Frank S. French^||, and Elizabeth M. Wilson^¶||**2

From the Laboratories for Reproductive Biology, Lineberger Comprehensive Cancer Center, and the Departments of ^¶Pathology, ^||Pediatrics, and ^**Biochemistry and Biophysics, University of North Carolina, Chapel Hill, North Caroina 27599

The androgen receptor (AR) is required for prostate cancer development and contributes to tumor progression after remission in response to androgen deprivation therapy. Epidermal growth factor (EGF) increases AR transcriptional activity at low levels of androgen in the CWR-R1 prostate cancer cell line derived from the castration-recurrent CWR22 prostate cancer xenograft. Here we report that knockdown of AR decreases EGF stimulation of prostate cancer cell growth and demonstrate a mechanistic link between EGF and AR signaling. The EGF-induced increase in AR transcriptional activity is dependent on phosphorylation at mitogen-activated protein kinase consensus site Ser-515 in the AR NH₂-terminal region and at protein kinase C consensus site Ser-578 in the AR DNA binding domain. Phosphorylation at these sites alters the nuclear-cytoplasmic shuttling of AR and AR interaction with the Ku-70/80 regulatory subunits of DNA-dependent protein kinase. Abolishing AR Ser-578 phosphorylation by introducing an S578A mutation eliminates the AR transcriptional response to EGF and increases both AR binding of Ku-70/80 and nuclear retention of AR in association with hyperphosphorylation of AR Ser-515. The results support a model in which AR transcriptional activity increases castration-recurrent prostate cancer cell growth in response to EGF by site-specific serine phosphorylation that regulates nuclear-cytoplasmic shuttling through interactions with the Ku-70/80 regulatory complex.

Received for publication, March 27, 2008 , and in revised form, May 21, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants HD16910 (NICHD, to United States Public Health Service) and P01-CA77739 (NCI). This work was also supported by United States Department of Defense Grant PC060628. 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 Present address: Clinsys Clinical Research, 8540 Colonnade Center Dr., Suite 501, Raleigh, NC 27615.

² To whom correspondence should be addressed: Laboratories for Reproductive Biology, CB7500, University of North Carolina, Chapel Hill, NC 27599-7500. Tel.: 919-966-5168; Fax: 919-966-2203; E-mail: emw{at}med.unc.edu.

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

This article has been cited by other articles:

				A. R. Karpf, S. Bai, S. R. James, J. L. Mohler, and E. M. Wilson Increased Expression of Androgen Receptor Coregulator MAGE-11 in Prostate Cancer by DNA Hypomethylation and Cyclic AMP Mol. Cancer Res., April 1, 2009; 7(4): 523 - 535. [Abstract] [Full Text] [PDF]

				J.-C. Pignon, B. Koopmansch, G. Nolens, L. Delacroix, D. Waltregny, and R. Winkler Androgen Receptor Controls EGFR and ERBB2 Gene Expression at Different Levels in Prostate Cancer Cell Lines Cancer Res., April 1, 2009; 69(7): 2941 - 2949. [Abstract] [Full Text] [PDF]

				S. Kaikkonen, T. Jaaskelainen, U. Karvonen, M. M. Rytinki, H. Makkonen, D. Gioeli, B. M. Paschal, and J. J. Palvimo SUMO-Specific Protease 1 (SENP1) Reverses the Hormone-Augmented SUMOylation of Androgen Receptor and Modulates Gene Responses in Prostate Cancer Cells Mol. Endocrinol., March 1, 2009; 23(3): 292 - 307. [Abstract] [Full Text] [PDF]

				A. E. Rosenblatt and K. L. Burnstein Inhibition of Androgen Receptor Transcriptional Activity as a Novel Mechanism of Action of Arsenic Mol. Endocrinol., March 1, 2009; 23(3): 412 - 421. [Abstract] [Full Text] [PDF]

				O. A. O'Mahony, M. P. Steinkamp, M. A. Albertelli, M. Brogley, H. Rehman, and D. M. Robins Profiling Human Androgen Receptor Mutations Reveals Treatment Effects in a Mouse Model of Prostate Cancer Mol. Cancer Res., November 1, 2008; 6(11): 1691 - 1701. [Abstract] [Full Text] [PDF]