Induction and superinduction of 2,3,7,8-tetrachlorodibenzo-rho-dioxin-inducible poly(ADP-ribose) polymerase: role of the aryl hydrocarbon receptor/aryl hydrocarbon receptor nuclear translocator transcription activation domains and a labile transcription repressor.
The environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induces a novel poly(ADP-ribose) polymerase (TiPARP). In this study, the signaling pathway of the induction was analyzed. Induction of TiPARP by TCDD occurs in both hepa1c1c7 cells and C57 mouse liver. Induction is concentration and time dependent. Genetic analyses reveal that induction is abolished in aromatic hydrocarbon receptor (AhR)- or aromatic hydrocarbon receptor nuclear translocator (Arnt)-defective variants but restored upon reconstitution of the variant cells with cDNAs expressing functional AhR or Arnt. Moreover, induction is largely reduced in cells expressing a deletion mutant of AhR or Arnt lacking the transcription activation (TA) domain, thus implicating the TA activities of both AhR and Arnt in the induction. Inhibition of protein synthesis by cycloheximide enhances the induction of TiPARP in the presence of an AhR agonist. The superinduction is transcriptional and does not require pretreatment with TCDD. Finally, inhibition of the 26S proteasomes by MG132 superinduces TiPARP. These findings establish that induction of TiPARP by TCDD is mediated through an AhR and Arnt transcription activation-dependent signal transduction that is repressed by a labile factor through the ubiquitin-26S proteasome-mediated protein degradation.
Ma
Qiang
Q
Receptor Biology Laboratory, Toxicology and Molecular Biology Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, Morgantown, WV 26505, USA. qam1@cdc.gov
D000818:Animals; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D002478:Cells, Cultured; D003433:Crosses, Genetic; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004268:DNA-Binding Proteins; D004790:Enzyme Induction / Q000187:drug effects*; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D007976:Leupeptins / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016297:Mutagenesis, Site-Directed; D010447:Peptide Hydrolases / Q000187:drug effects; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism*; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex; D017434:Protein Structure, Tertiary / Q000502:physiology; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects
C497397:Arnt protein, mouse; D015853:Cysteine Proteinase Inhibitors; D004268:DNA-Binding Proteins; D007976:Leupeptins; D000072317:Polychlorinated Dibenzodioxins; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D014157:Transcription Factors; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D011065:Poly(ADP-ribose) Polymerases; D010447:Peptide Hydrolases; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde