Thyroid hormone response elements differentially modulate the interactions of thyroid hormone receptors with two receptor binding domains in the steroid receptor coactivator-1.

Published

Journal Article

Ligand-dependent transcriptional activation by nuclear receptors is mediated by interactions with coactivators. Recently, a consensus interaction motif (LXXLL) has been identified in a number of coactivators such as steroid receptor coactivator-1 (SRC-1). SRC-1 contains three such motifs in the central (nuclear receptor binding domain-1, NBD-1) and a single one in the C-terminal (NBD-2) regions. To define the nature and role of the two NBDs in SRC-1, interaction studies between the two NBDs and thyroid hormone receptor (TR) were performed. Although NBD-1 and NBD-2 showed similar ligand- and AF-2-dependent interactions with TR in solution, these two NBDs possessed distinct interaction properties with TR when TR is bound to a thyroid hormone-response element (TRE). Both in vitro and in vivo interaction studies demonstrate that NBD-1, but not NBD-2, exhibits ligand-dependent interaction with TR in the presence of TREs. In addition, a natural isoform of SRC-1, SRC-1E, which lacks NBD-2, preserved TR as well as progesterone receptor-mediated coactivator function on reporter gene expression. Finally, we found that NBD-1 failed to interact with a TR and retinoid X receptor heterodimer complex on a transcriptionally inactive direct repeat +4 TRE in electrophoretic mobility shift assays. These observations indicate that DNA-induced, as well as ligand-induced, conformational change(s) of TR may influence the nature of its binding to SRC-1, and that the two NBDs of SRC-1 may play different roles to regulate ligand-dependent transactivation of TRs.

Full Text

Duke Authors

Cited Authors

  • Takeshita, A; Yen, PM; Ikeda, M; Cardona, GR; Liu, Y; Koibuchi, N; Norwitz, ER; Chin, WW

Published Date

  • August 21, 1998

Published In

Volume / Issue

  • 273 / 34

Start / End Page

  • 21554 - 21562

PubMed ID

  • 9705285

Pubmed Central ID

  • 9705285

International Standard Serial Number (ISSN)

  • 0021-9258

Digital Object Identifier (DOI)

  • 10.1074/jbc.273.34.21554

Language

  • eng

Conference Location

  • United States