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.
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 (23)FQNLF(27) 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.
Need
Eleanor F
EF
Molecular Ageing Laboratory, Freemasons Foundation Centre for Mens Health, Dame RomaMitchell Cancer Research Laboratories, University of Adelaide/Hanson Institute, Adelaide, Australia.
Scher
Howard I
HI
Peters
Amelia A
AA
Moore
Nicole L
NL
Cheong
Albert
A
Ryan
Charles J
CJ
Wittert
Gary A
GA
Marshall
Villis R
VR
Tilley
Wayne D
WD
Buchanan
Grant
G
D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D002843:Chromatin / Q000235:genetics* / Q000502:physiology; D018450:Disease Progression; D014644:Genetic Variation / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D054730:Protein Interaction Domains and Motifs / Q000235:genetics* / Q000502:physiology; D011944:Receptors, Androgen / Q000235:genetics* / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology
D002843:Chromatin; D011944:Receptors, Androgen