Mutation of Histidine 874 in the Androgen Receptor Ligand Binding Domain Leads to Promiscuous Ligand Activation and Altered p160 Coactivator Interactions

Jennifer Duff, Iain Joseph McEwan

Research output: Contribution to journalArticlepeer-review

70 Citations (Scopus)

Abstract

The androgen receptor (AR) signaling pathway is a major therapeutic target in the treatment of prostate cancer. The AR functions as a ligand-activated transcription factor in the presence of the cognate hormone ligands testosterone and dihydrotestosterone (DHT). We have characterized a highly conserved sequence at the C-terminal end of helix 10/11 in the ligand-binding domain (LBD), which is prone to receptor point mutations in prostate cancer. This sequence includes threonine 877 that is involved in hydrogen bonding to the D ring of the steroid molecule and leads to promiscuous ligand activation of the AR when mutated to alanine or serine. A second mutation in this region, H874Y, also results in a receptor protein that has broadened ligand-binding specificity, but retains an affinity for DHT (K-d = 0.77 nM) similar to that of the wild-type receptor. The structure of the mutant LBD, expressed in Escherichia coli, is not dramatically altered compared with the wild-type AR-LBD in the presence of DHT, but shows a modestly increased sensitivity to protease digestion in the absence of hormone. This mutant AR showed wildtype AR-LBD/N-terminal domain interactions, but significantly enhanced binding and transactivation activity with all three members of the p160 family of coactivator proteins. Together, these phenotypic changes are likely to confer a selective advantage for tumor cells in a low androgen environment resulting from hormone therapy.

Original languageEnglish
Pages (from-to)2943-2954
Number of pages11
JournalMolecular Endocrinology
Volume19
DOIs
Publication statusPublished - 2005

Keywords

  • HUMAN PROSTATE-CANCER
  • GENE-MUTATIONS
  • TRANSCRIPTIONAL ACTIVATION
  • TERMINAL INTERACTION
  • DEPRIVATION THERAPY
  • LNCAP CELLS
  • PROGRESSION
  • AMPLIFICATION
  • SPECIFICITY
  • EXPRESSION

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