Unique requirements for retinoid-dependent transcriptional activation by the orphan receptor LXR

Patricia J. Willy, David J. Mangelsdorf

Research output: Contribution to journalArticle

130 Citations (Scopus)

Abstract

LXR is an orphan nuclear receptor that confers retinoid responsiveness to the retinoid X receptor (RXR) by its interaction on a specific response element called an LXRE. To understand the mechanism of this response, three characteristics were identified that are crucial to activation of the RXR- LXR complex. First, the orientation of the RXR-LXR heterodimer on DNA indicates that as the ligand-binding partner, RXR occupies the 5' half-site of the response element. Next, the sequence specificity of the LXRE was determined in order to identify residues required for retinoid activation of the heterodimer. Remarkably, subtle changes in the nucleotide sequence of the LXRE half-sites that do not substantially alter DNA binding of the RXR-LXR heterodimer have a significant effect on the ability of the complex to be activated by ligand. Finally, we characterized the contributions of the activation domains of each receptor to the trans.activation potential of the RXR-LXR heterodimer. Surprisingly, our results show that only the activation domain of LXR is required for retinoid activation. Taken together, these results demonstrate the existence of a unique form of communication between heterodimer partners in which the activation potential of one receptor (LXR) is enabled by ligand binding to its partner (RXR). Furthermore, we conclude that RXR ligand activation potential is not dictated solely by its position on DNA, but is influenced by other factors such as the receptor partner and sequence of the response element.

Original languageEnglish (US)
Pages (from-to)289-298
Number of pages10
JournalGenes and Development
Volume11
Issue number3
StatePublished - Feb 1 1997

Fingerprint

Retinoid X Receptors
Retinoids
Transcriptional Activation
Response Elements
Ligands
DNA
Orphan Nuclear Receptors

Keywords

  • heterodimers
  • LXR
  • nuclear receptors
  • retinoid receptors
  • RXR
  • trans-activation domain

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

Cite this

Unique requirements for retinoid-dependent transcriptional activation by the orphan receptor LXR. / Willy, Patricia J.; Mangelsdorf, David J.

In: Genes and Development, Vol. 11, No. 3, 01.02.1997, p. 289-298.

Research output: Contribution to journalArticle

@article{7473b4afc54146a29ee60bae1112c256,
title = "Unique requirements for retinoid-dependent transcriptional activation by the orphan receptor LXR",
abstract = "LXR is an orphan nuclear receptor that confers retinoid responsiveness to the retinoid X receptor (RXR) by its interaction on a specific response element called an LXRE. To understand the mechanism of this response, three characteristics were identified that are crucial to activation of the RXR- LXR complex. First, the orientation of the RXR-LXR heterodimer on DNA indicates that as the ligand-binding partner, RXR occupies the 5' half-site of the response element. Next, the sequence specificity of the LXRE was determined in order to identify residues required for retinoid activation of the heterodimer. Remarkably, subtle changes in the nucleotide sequence of the LXRE half-sites that do not substantially alter DNA binding of the RXR-LXR heterodimer have a significant effect on the ability of the complex to be activated by ligand. Finally, we characterized the contributions of the activation domains of each receptor to the trans.activation potential of the RXR-LXR heterodimer. Surprisingly, our results show that only the activation domain of LXR is required for retinoid activation. Taken together, these results demonstrate the existence of a unique form of communication between heterodimer partners in which the activation potential of one receptor (LXR) is enabled by ligand binding to its partner (RXR). Furthermore, we conclude that RXR ligand activation potential is not dictated solely by its position on DNA, but is influenced by other factors such as the receptor partner and sequence of the response element.",
keywords = "heterodimers, LXR, nuclear receptors, retinoid receptors, RXR, trans-activation domain",
author = "Willy, {Patricia J.} and Mangelsdorf, {David J.}",
year = "1997",
month = "2",
day = "1",
language = "English (US)",
volume = "11",
pages = "289--298",
journal = "Genes and Development",
issn = "0890-9369",
publisher = "Cold Spring Harbor Laboratory Press",
number = "3",

}

TY - JOUR

T1 - Unique requirements for retinoid-dependent transcriptional activation by the orphan receptor LXR

AU - Willy, Patricia J.

AU - Mangelsdorf, David J.

PY - 1997/2/1

Y1 - 1997/2/1

N2 - LXR is an orphan nuclear receptor that confers retinoid responsiveness to the retinoid X receptor (RXR) by its interaction on a specific response element called an LXRE. To understand the mechanism of this response, three characteristics were identified that are crucial to activation of the RXR- LXR complex. First, the orientation of the RXR-LXR heterodimer on DNA indicates that as the ligand-binding partner, RXR occupies the 5' half-site of the response element. Next, the sequence specificity of the LXRE was determined in order to identify residues required for retinoid activation of the heterodimer. Remarkably, subtle changes in the nucleotide sequence of the LXRE half-sites that do not substantially alter DNA binding of the RXR-LXR heterodimer have a significant effect on the ability of the complex to be activated by ligand. Finally, we characterized the contributions of the activation domains of each receptor to the trans.activation potential of the RXR-LXR heterodimer. Surprisingly, our results show that only the activation domain of LXR is required for retinoid activation. Taken together, these results demonstrate the existence of a unique form of communication between heterodimer partners in which the activation potential of one receptor (LXR) is enabled by ligand binding to its partner (RXR). Furthermore, we conclude that RXR ligand activation potential is not dictated solely by its position on DNA, but is influenced by other factors such as the receptor partner and sequence of the response element.

AB - LXR is an orphan nuclear receptor that confers retinoid responsiveness to the retinoid X receptor (RXR) by its interaction on a specific response element called an LXRE. To understand the mechanism of this response, three characteristics were identified that are crucial to activation of the RXR- LXR complex. First, the orientation of the RXR-LXR heterodimer on DNA indicates that as the ligand-binding partner, RXR occupies the 5' half-site of the response element. Next, the sequence specificity of the LXRE was determined in order to identify residues required for retinoid activation of the heterodimer. Remarkably, subtle changes in the nucleotide sequence of the LXRE half-sites that do not substantially alter DNA binding of the RXR-LXR heterodimer have a significant effect on the ability of the complex to be activated by ligand. Finally, we characterized the contributions of the activation domains of each receptor to the trans.activation potential of the RXR-LXR heterodimer. Surprisingly, our results show that only the activation domain of LXR is required for retinoid activation. Taken together, these results demonstrate the existence of a unique form of communication between heterodimer partners in which the activation potential of one receptor (LXR) is enabled by ligand binding to its partner (RXR). Furthermore, we conclude that RXR ligand activation potential is not dictated solely by its position on DNA, but is influenced by other factors such as the receptor partner and sequence of the response element.

KW - heterodimers

KW - LXR

KW - nuclear receptors

KW - retinoid receptors

KW - RXR

KW - trans-activation domain

UR - http://www.scopus.com/inward/record.url?scp=0031042762&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0031042762&partnerID=8YFLogxK

M3 - Article

VL - 11

SP - 289

EP - 298

JO - Genes and Development

JF - Genes and Development

SN - 0890-9369

IS - 3

ER -