This Article Full Text Full Text (PDF) Supplemental Data Alert me when this article is cited 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 Copyright Permission Google Scholar Articles by Need, E. F. Articles by Buchanan, G. PubMed PubMed Citation Articles by Need, E. F. Articles by Buchanan, G.

A Novel Androgen Receptor Amino Terminal Region Reveals Two Classes of Amino/Carboxyl Interaction-Deficient Variants with Divergent Capacity to Activate Responsive Sites in Chromatin

Molecular Ageing Laboratory (E.F.N., V.R.M., G.B.), Freemasons Foundation Centre for Mens Health, Dame Roma Mitchell Cancer Research Laboratories (E.F.N., A.A.P., N.L.M., A.C., W.D.T., G.B.), University of Adelaide/Hanson Institute, and University of Adelaide, School of Medicine and Royal Adelaide Hospital (G.A.W.), Adelaide 5005, Australia; Genitourinary Oncology Service (H.I.S.), Division of Solid Tumor Oncology, Memorial Sloan-Kettering Cancer Center, Joan and Sanford I. Weill College of Medicine, New York, New York 10021; and The Urologic Oncology Program (C.J.R.), Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California 94143

Address all correspondence and requests for reprints to: Grant Buchanan, Molecular Ageing Laboratory, Freemasons Foundation Centre for Mens Health, University of Adelaide/Hanson Institute, Level 5, Eleanor Harrald Building, EH5-11, Adelaide, South Australia 5005, Australia. E-mail: grant.buchanan{at}adelaide.edu.au.

The androgen receptor (AR) is an important signaling molecule in multiple tissues, yet its mode of action and cell-specific activities remain enigmatic. AR function has been best studied in the prostate, in which it is essential for growth and homeostasis of the normal organ as well as each stage of cancer development. Investigation of mechanisms responsible for continued AR action that evolve during prostate cancer progression or after hormonal management of the disease have been instructive in defining AR signaling pathways. In the current paper, we use sequence similarity and the collocation of somatic mutations in prostate cancer to define residues 501–535 of the AR amino-terminal domain as an important mediator of receptor function. Specifically, the 501–535 region is required for optimal interaction of the amino-terminal domain with both the p160 coactivator, nuclear receptor coactivator-2, and the AR-ligand binding domain in the amino/carboxyl (N/C) interaction. The N/C interaction is decreased by deletion of the 501–535 region but is distinct from deletion of the ²³FQNLF²⁷ peptide in that it does not affect the capacity of the AR to activate transcription from a chromatin integrated reporter or recruitment of the receptor to androgen-responsive loci in vivo. Collectively, we have been able to outline two classes of N/C-deficient AR variant that are divergent in their capacity to act in a chromatin context, thereby further defining the interplay between N/C interaction and coregulator recruitment via multiple receptor domains. These mechanisms are likely to be key determinants of the cell and promoter specific activities of the AR.