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J Biol Chem, Vol. 274, Issue 51, 36351-36356, December 17, 1999
From the Department of Biochemistry, University of Adelaide,
Adelaide, South Australia, Australia 5005
The basic helix-loop-helix/Per-ARNT-Sim homology
domain dioxin receptor (DR) translocates to the nucleus upon binding of
aromatic hydrocarbon ligands typified by dioxin, whereupon it partners the Ah receptor nuclear translocator and initiates transcription. Concurrently, ligand binding down-regulates receptor levels via an
unknown mechanism. In this study we show that receptor levels are
dependent upon cellular compartmentalization, with entry into the
nucleus leading to the rapid destruction of the DR. Ligand-induced DR
translocation was bypassed by adding a heterologous nuclear localization signal to the DR, creating a constitutively nuclear form
of the dioxin receptor (DRNLS). The DRNLS protein was shown to be
unstable with a half-life of
Degradation of the Basic Helix-Loop-Helix/Per-ARNT-Sim
Homology Domain Dioxin Receptor Via the Ubiquitin/Proteasome
Pathway*
§ and
1 h whether partnering ARNT or HSP90.
Thus, the structural changes induced by ligand binding have no inherent
effect on DR stability but are critical in transporting the receptor
prior to degradation. The proteolytic pathway that degrades the nuclear
receptor is suggested to involve ubiquitination as it was inhibited by
the proteasome inhibitor MG132 or co-expression of DRNLS with the
ubiquitin mutant UbK48R. Incubation of cells expressing DRNLS with the
phosphatase inhibitor calyculin resulted in the rapid
phosphorylation and ubiquitination of DRNLS, suggesting that a nuclear
kinase is required to trigger receptor proteolysis. Overall, this study
demonstrates a novel mechanism of proteolysis whereby the simple
relocation of a transcription factor from cytoplasm to nucleus
initiates its rapid destruction.
*
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Present address: School of Pharmacy and Medical Sciences,
University of South Australia, Adelaide, South Australia, Australia 5000.
§
To whom correspondence should be addressed: Dept. of Biochemistry,
University of Adelaide, Adelaide, South Australia, Australia 5005. Tel.: 61-8-8303472; Fax: 61-8-83034348; E-mail: broberts@biochem. adelaide.edu.au.
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