Delineation of two distinct type 1 activation functions in the androgen receptor amino-terminal domain

Nancy L. Chamberlain, David C. Whitacre, Roger L. Miesfeld

Research output: Contribution to journalArticle

95 Scopus citations

Abstract

Based on the finding that some transcription factors contain multiple transcriptional regulatory activities, we constructed a panel of rat androgen receptor (AR) mutants containing small internal deletions and point mutations within the amino-terminal region of the receptor. Trans-activation assays in CV-1 cells using AR-responsive reporter genes were performed and led to the identification of two noncontiguous trans-activation regions in the AR amino terminus. One of these regions, termed activator function 1a (AF-1a) is a highly-conserved 14-amino acid segment that is predicted to form a β-turn followed by an acidic amphipathic α-helix. Point mutagenesis within AF-1a revealed that two adjacent hydrophobic residues were required for full AR transactivation function, as arginine substitutions resulted in a 60% reduction in transcriptional activity. A second amino-terminal region was also identified and has been designated AF-1b. Deletion of the 65-amino acid AF-1b segment, which contains numerous glutamate and aspartate residues, caused a 55% decrease in trans-activation function. An AF-1a/AF-1b double mutant retains less than 10% trans-activation function compared with wild- type AR, suggesting that AF-1a and AF-1b may each contribute separately to maximal AR activity. To determine whether AF-1a and AF-1b play a role in AR- mediated trans-repression of AP-1 function, we tested single and double AF- 1a/AF-1b mutants in a transient trans-repression assay. Our results showed that neither AF-1a nor AF-1b was required for AP-1 trans-repression, demonstrating that AR-mediated trans-repression and trans-activation are discrete functions.

Original languageEnglish (US)
Pages (from-to)26772-26778
Number of pages7
JournalJournal of Biological Chemistry
Volume271
Issue number43
DOIs
StatePublished - 1996

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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