Quantitative differences in androgen and glucocorticoid receptor DNA binding properties contribute to receptor-selective transcriptional regulation

Stephen E. Rundlett, Roger L. Miesfeld

Research output: Contribution to journalArticle

49 Scopus citations

Abstract

Androgen receptor (AR) and glucocorticoid receptor (GR) belong to the same subfamily of steroid/nuclear receptors and have been shown to bind qualitatively to the same hormone response element (HRE) DNA sequences. Despite this similarity in target gene recognition, AR and GR have differential affects on the transcriptional regulation of genes containing both simple and complex HRE control regions. Using HREs from the mouse mammary tumor virus (MMTV), tyrosine aminotransferase (TAT), prostatein (C3) or sexlimited protein (SLP) genes, linked to the thymidine kinase promoter, we found receptor-selective differences in the ability of rat AR and rat GR to induce transcription of these various reporter genes. Since AR and GR have a 20% amino acid sequence difference in their DNA binding domains (DBDs), which could result in altered DNA binding affinities, we measured the ability of purified AR and GR DBDs to bind selectively and with high affinity to these HRE sequences in vitro. Gel shift mobility assays showed that the GR DBD had a higher affinity for a consensus HRE than did the AR DBD, and quantitative DNase I footprinting revealed that AR and GR DBDs bound to the MMTV, TAT, C3 and SLP HREs with different affinities. It was found that AR had a dissociation constant (Kd) that was 2-3 times higher than GR on the TAT, C3 and SLP HREs and that the Kd of AR for the C3 and SLP HREs differed by an order of magnitude (43 nM and 460 nM, respectively). Taken together, these data suggest that amino acid differences in the AR and GR DBDs contribute to altered receptor-DNA interactions, however it is likely that non-receptor factors are involved in further modulating receptor-selective DNA binding and transactivation functions.

Original languageEnglish (US)
Pages (from-to)1-10
Number of pages10
JournalMolecular and Cellular Endocrinology
Volume109
Issue number1
DOIs
StatePublished - Mar 1995

Keywords

  • Androgen receptor
  • DNA binding affinities
  • Glucocorticoid receptor
  • Steroid-regulated gene expression

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Endocrinology

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