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Multiple roles of ligand in transforming the dioxin receptor to an active basic helix-loop-helix/PAS transcription

M J Lees1, M L Whitelaw

  • 1Department of Biochemistry, University of Adelaide, Adelaide 5005, South Australia, Australia.

Molecular and Cellular Biology
|July 20, 1999
PubMed

Insights

Ligand binding to the dioxin receptor (DR) is crucial for its nuclear translocation, Arnt dimerization, and maintaining structural integrity for transcriptional activation. This study reveals multiple roles for ligands in DR activation beyond nuclear import.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • The dioxin receptor (DR) is a ligand-activated transcription factor.
  • DR belongs to the basic helix-loop-helix/PAS protein family.
  • DR interacts with hsp90 in latent states and heterodimerizes with Arnt for DNA binding.

Purpose of the Study:

  • To investigate the functional roles of ligands in dioxin receptor activation beyond nuclear import.
  • To elucidate the mechanism of dioxin receptor transformation and transcriptional activation.

Main Methods:

  • Created a cell line expressing a constitutively nuclear dioxin receptor.
  • Utilized dioxin and geldanamycin (hsp90 ligand) for receptor transformation.
  • Employed proteasome inhibitors and limited proteolysis for mechanistic studies.

Main Results:

  • Ligand binding is essential for DR nuclear translocation, Arnt dimerization, and maintaining transcriptional competence.
  • Geldanamycin treatment leads to rapid degradation of the unchaperoned dioxin receptor.
  • Artificial transformation with geldanamycin yields a DNA-binding but transcriptionally inactive DR-Arnt complex, indicating distinct conformations.

Conclusions:

  • Ligands play multiple, critical roles in dioxin receptor activation, including nuclear import, Arnt heterodimerization, and maintaining structural integrity for transcription.
  • The molecular chaperone hsp90 is released from the ligand-bound dioxin receptor during nuclear activation.
  • Distinct ligand-induced conformations of the DR-Arnt complex dictate transcriptional activity.

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