spacer gif spacer gif spacer gif spacer gif spacer gif
QUICK SEARCH:   [advanced]


spacer gif
     Home     Help     Feedback     Subscriptions     Archive     Search    

The fully linked HTML version of this article has now been published.
JCS ePress online publication date 1 Sep 2005
doi: 10.1242/jcs.02546

This Article
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
jcs.02546v1
118/18/4187    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Farla, P.
Right arrow Articles by Houtsmuller, A. B.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Farla, P.
Right arrow Articles by Houtsmuller, A. B.

Research Article

Antiandrogens prevent stable DNA-binding of the androgen receptor


Pascal Farla, Remko Hersmus, Jan Trapman, and Adriaan B. Houtsmuller*
* Author for correspondence (e-mail: a.houtsmuller{at}erasmusmc.nl)

The androgen receptor (AR) is essential for development of the male gender and in the growth of the majority of prostate cancers. Agonists as well as most antagonists induce translocation of the receptor to the nucleus, whereas only agonists can activate AR function. Antagonists are therefore used in the therapy of metastasized prostate cancer. To obtain insight into the mechanism by which antagonists block AR function in living cells, we studied nuclear mobility and localization of green fluorescent protein (GFP)-tagged AR in the presence of either the agonist R1881 or the antagonists bicalutamide and hydroxyflutamide. As controls we investigated a non-DNA-binding AR mutant (A573D) and two mutants (W741C and T877A) with broadened ligand specificity. We demonstrate that in the presence of R1881, AR localizes in numerous intranuclear foci and, using complementary fluorescence recovery after photobleaching (FRAP) approaches and computer modelling, that a fraction of AR (~10-15%) is transiently immobilized in a DNA-binding-dependent manner (individual ARs being immobile for ~45 seconds). By contrast, antagonist-bound GFP-AR showed no detectable immobile fraction and the mobility was similar to that of the R1881-liganded non-DNA-binding mutant (A573D), indicating that antagonists do not induce the relatively stable DNA-binding-dependent immobilization observed with agonist-bound AR. Moreover, in the presence of bicalutamide and hydroxyflutamide GFP-AR was homogeneously distributed in the nucleus. Binding of bicalutamide and hydroxyflutamide to GFP-AR(W741C) and GFP-AR(T877A), respectively, resulted in similar mobility and heterogeneous nuclear distribution as observed for R1881-liganded GFP-AR. The live cell studies indicate that the investigated antagonists interfere with events early in the transactivation function of the AR.


This article has been cited by other articles:


Home page
 Mol. Biol. CellHome page
T. A. Johnson, C. Elbi, B. S. Parekh, G. L. Hager, and S. John
Chromatin Remodeling Complexes Interact Dynamically with a Glucocorticoid Receptor-regulated Promoter
Mol. Biol. Cell, August 1, 2008; 19(8): 3308 - 3322.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
L. C. Shank, J. B. Kelley, D. Gioeli, C.-S. Yang, A. Spencer, L. A. Allison, and B. M. Paschal
Activation of the DNA-dependent Protein Kinase Stimulates Nuclear Export of the Androgen Receptor in Vitro
J. Biol. Chem., April 18, 2008; 283(16): 10568 - 10580.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
W. H. Bisson, A. V. Cheltsov, N. Bruey-Sedano, B. Lin, J. Chen, N. Goldberger, L. T. May, A. Christopoulos, J. T. Dalton, P. M. Sexton, et al.
Discovery of antiandrogen activity of nonsteroidal scaffolds of marketed drugs
PNAS, July 17, 2007; 104(29): 11927 - 11932.
[Abstract] [Full Text] [PDF]

Home page
 J. Histochem. Cytochem.Home page
H. Nakauchi, K.-i. Matsuda, I. Ochiai, A. Kawauchi, Y. Mizutani, T. Miki, and M. Kawata
A Differential Ligand-mediated Response of Green Fluorescent Protein-tagged Androgen Receptor in Living Prostate Cancer and Non-prostate Cancer Cell Lines
J. Histochem. Cytochem., June 1, 2007; 55(6): 535 - 544.
[Abstract] [Full Text] [PDF]

Home page
 JCBHome page
M. E. van Royen, S. M. Cunha, M. C. Brink, K. A. Mattern, A. L. Nigg, H. J. Dubbink, P. J. Verschure, J. Trapman, and A. B. Houtsmuller
Compartmentalization of androgen receptor protein-protein interactions in living cells
J. Cell Biol., April 9, 2007; 177(1): 63 - 72.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Cell. Biol.Home page
T. I. Klokk, P. Kurys, C. Elbi, A. K. Nagaich, A. Hendarwanto, T. Slagsvold, C.-Y. Chang, G. L. Hager, and F. Saatcioglu
Ligand-Specific Dynamics of the Androgen Receptor at Its Response Element in Living Cells
Mol. Cell. Biol., March 1, 2007; 27(5): 1823 - 1843.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
C. Tudor, J. N. Feige, H. Pingali, V. B. Lohray, W. Wahli, B. Desvergne, Y. Engelborghs, and L. Gelman
Association with Coregulators Is the Major Determinant Governing Peroxisome Proliferator-activated Receptor Mobility in Living Cells
J. Biol. Chem., February 16, 2007; 282(7): 4417 - 4426.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
Y.-C. Chuan, S.-T. Pang, A. Cedazo-Minguez, G. Norstedt, A. Pousette, and A. Flores-Morales
Androgen Induction of Prostate Cancer Cell Invasion Is Mediated by Ezrin
J. Biol. Chem., October 6, 2006; 281(40): 29938 - 29948.
[Abstract] [Full Text] [PDF]


© The Company of Biologists Ltd 2005