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2,3,7,8-tetrachlorodibenzo-p-dioxin-induced degradation of aryl hydrocarbon receptor (AhR) by the ubiquitin-proteasome pathway: role of the transcription activaton and DNA binding of AhR.

Authors
Ma-Q; Baldwin-KT
Source
J Biol Chem 2000 Mar; 275(12):8432-8438
NIOSHTIC No.
20020742
Abstract
Activation of the aryl hydrocarbon receptor (AhR) by 2,3,7, 8-tetrachlorodibenzo-p-dioxin (TCDD), a potent agonist of AhR, induces a marked reduction in steady state AhR. To analyze the mechanism of regulation of ligand-activated AhR, we examined the biochemical pathway and function of the down-regulation of the receptor by TCDD. Pulse-chase experiments reveal that TCDD shortens the half-life (t1/2) of AhR from 28 to 3 h in mouse hepatoma cells. Inhibitors of the 26 S proteasome, lactacystin and MG132, block the TCDD-induced turnover of AhR. The TCDD-induced degradation of AhR involves ubiquitination of the AhR protein, because (a) TCDD induces formation of high molecular weight, ubiquitinated AhR and (b) degradation of AhR is inhibited in ts20 cells, which bear a temperature-sensitive mutation in the ubiquitin-activating enzyme E1, at a nonpermissive temperature. Inhibition of proteasomal degradation of AhR increases the amount of the nuclear AhR.Arnt complex and "superinduces" the expression of endogenous CYP1A1 gene by TCDD, indicating that the proteasomal degradation of AhR serves as a mechanism for controlling the activity of the activated receptor. We also show that deletion of the transcription activation domain of AhR abolishes the degradation, whereas a mutation in the DNA-binding region of AhR or Arnt reduces the degradation; these data implicate the transcription activation domain and DNA binding in AhR degradation. Our findings provide new insights into the regulation of TCDD-activated AhR through ubiquitin-mediated protein degradation.
Keywords
Aryls; Arylamines; Hydrocarbons; Laboratory-animals; Animals; Animal-studies; Dioxins
Contact
CDC/NIOSH/HELD/TMBB, Mailstop 3014, 1095 Willowdale Road, Morgantown, WV 26505
CODEN
JBCHA3
CAS No.
1746-01-6
Publication Date
20000324
Document Type
Journal Article
Email Address
qam1@cdc.gov
Fiscal Year
2000
NTIS Accession No.
NTIS Price
Issue of Publication
12
ISSN
0021-9258
NIOSH Division
HELD
Source Name
Journal of Biological Chemistry
State
WV
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