| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on October 22, 2001
Accepted on August 27, 2002
1 Department of Molecular & Cellular Biology (A.J.J., I.U.A., M.M., D.J.L., N.L.W.), Scott Department of Urology (D.J.L.) and Department of Medicine (M.M.), Baylor College of Medicine, Houston, Texas 77030, Institute for Molecular Biosciences, University of Queensland, Brisbane QLD 4072, Australia (J.M.H.), Flinders Cancer Centre, Flinders University and Flinders Medical Centre, Adelaide SA 5042, Australia (G.B., W.D.T.)
* To whom correspondence should be addressed. E-mail: nweigel{at}bcm.tmc.edu.
Functional analysis of androgen receptor (AR) gene mutations isolated from prostate cancer has led to the identification of residues that play important roles in the structure and function of the receptor. Here we report the characteristics of a novel AR mutation A748T located in helix 5 of the ligand-binding domain, which was identified in metastatic prostate cancer. Despite a normal hormone-binding affinity, A748T causes hormone concentration-dependent defects in nuclear accumulation and transcriptional activation. Moreover, when equivalent amounts of DNA are transfected, the mutant is expressed at much lower levels than the wild type receptor (ARWT). Treatment with geldanamycin to disrupt receptor-heat shock protein complexes rapidly decreases the levels of ARWT but not A748T, suggesting that the lower expression and rapid degradation rate of A748T is due to weaker interactions with heat shock proteins. Further analysis revealed that hormone dissociates from A748T 5-times faster than from ARWT. Loss of the ability to form stable amino/carboxyl terminal interactions causes accelerated dissociation rates in some AR mutants. However, A748T exhibits normal amino/carboxyl terminal interactions at high hormone concentrations suggesting that the mutation alters interactions with ligand. Consistent with this conclusion, our structural model predicts that A748T disrupts crucial contact points with ligand, thereby altering the conformation of the ligand-binding domain.
NURSA Molecule Pages Link:
This article has been cited by other articles:
 |
|
 |
|
  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]
|
|
|
|
 |
|
 I. U. Agoulnik, A. Vaid, W. E. Bingman III, H. Erdeme, A. Frolov, C. L. Smith, G. Ayala, M. M. Ittmann, and N. L. Weigel Role of SRC-1 in the Promotion of Prostate Cancer Cell Growth and Tumor Progression Cancer Res., September 1, 2005; 65(17): 7959 - 7967. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z Culig, H Steiner, G Bartsch, and A Hobisch Mechanisms of endocrine therapy-responsive and -unresponsive prostate tumours Endocr. Relat. Cancer, June 1, 2005; 12(2): 229 - 244. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Yamamoto, N. K. Shevde, A. Warrier, L. A. Plum, H. F. DeLuca, and J. W. Pike 2-Methylene-19-nor-(20S)-1,25-dihydroxyvitamin D3 Potently Stimulates Gene-specific DNA Binding of the Vitamin D Receptor in Osteoblasts J. Biol. Chem., August 22, 2003; 278(34): 31756 - 31765. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
