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Type: Journal article
Title: Defining the role for XAP2 in stabilization of the dioxin receptor
Author: Lees, M.
Peet, D.
Whitelaw, M.
Citation: Journal of Biological Chemistry, 2003; 278(38):35878-35888
Publisher: Amer Soc Biochemistry Molecular Biology Inc
Issue Date: 2003
ISSN: 0021-9258
Organisation: Centre for the Molecular Genetics of Development
Statement of
Michael J. Lees, Daniel J. Peet and Murray L. Whitelaw
Abstract: The dioxin receptor (DR) is a ligand-activated transcription factor that is activated upon binding of dioxins or structurally related forms of xenobiotics. Upon binding ligand the DR translocates from the cytoplasm to the nucleus where it complexes with the partner protein Arnt to form a DNA binding heterodimer, which activates transcription of target genes involved in xenobiotic metabolism. Latency of the DR signaling pathway is maintained by association of the DR with a number of molecular chaperones including the 90-kDa heat shock protein (hsp90), the hepatitis B virus X-associated protein (XAP2), and the 23-kDa heat shock protein (p23). Here we investigated the role of XAP2 in DR signaling and demonstrated that reduced levels of XAP2 labilize the DR, arguing for a function of XAP2 beyond its reported role as a cytoplasmic retention factor. In addition, we showed that a constitutively nuclear DR is degraded in the nucleus and does not require nuclear export for efficient degradation. We also provided evidence implicating the ubiquitin ligase protein C-terminal hsp70-interacting protein (CHIP) in the degradation of the DR, and we demonstrated that this degradation can be overcome by overexpression of XAP2. XAP2 protection of CHIP-mediated degradation is dependent on the tetratricopeptide repeat domain of XAP2 and suggests a mechanism whereby competition for the C-terminal tetratricopeptide repeat acceptor site of hsp90 guides the protein triage decision, the point of determination for either maturation of DR folding or DR degradation.
Keywords: Cell Line
Cell Nucleus
Ubiquitin-Protein Ligases
Intracellular Signaling Peptides and Proteins
Luminescent Proteins
Green Fluorescent Proteins
Receptors, Aryl Hydrocarbon
Oligonucleotides, Antisense
Microscopy, Fluorescence
Electrophoresis, Polyacrylamide Gel
Signal Transduction
Transcription, Genetic
Gene Deletion
Binding Sites
Protein Structure, Tertiary
Protein Binding
Protein Folding
Active Transport, Cell Nucleus
Dose-Response Relationship, Drug
Genetic Vectors
Models, Genetic
HSP70 Heat-Shock Proteins
HSP90 Heat-Shock Proteins
Description: © 2003 by The American Society for Biochemistry and Molecular Biology
DOI: 10.1074/jbc.M302430200
Published version:
Appears in Collections:Aurora harvest 6
Centre for the Molecular Genetics of Development publications
Molecular and Biomedical Science publications

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