Multiple mechanisms are involved in Ah receptor-mediated cell cycle arrest.
The liver is the only solid organ that can respond to major tissue loss or damage by regeneration to restore liver biomass. The aryl hydrocarbon receptor (AhR) agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) can disrupt the regenerative process, as evidenced by suppression of DNA synthesis in rat primary hepatocytes in culture and in vivo liver regeneration after partial hepatectomy. Independent observations demonstrated that AhR-mediated G(1) phase cell cycle arrest depends on an interaction with the retinoblastoma tumor suppressor protein (pRb), but differences exist regarding proposed mechanisms of action. Two distinct models have been proposed, one supporting the AhR-pRb interaction functioning in corepression of E2F activity and the other favoring an AhR-pRb interaction participating in transcriptional coactivation of genes encoding G(1) phase regulatory proteins. In the present study, experiments in rat hepatoma cells using dominant-negative DNA-binding-defective AhR and Ah receptor nuclear translocator (Arnt) mutants provided evidence that TCDD-induced AhR-mediated G(1) arrest is only partially regulated by direct AhR transcriptional activity, suggesting that both coactivation and corepression are involved. Studies using a small interfering RNA to down-regulate Arnt protein expression revealed that TCDD-induced G(1) arrest is absolutely dependent on the Arnt protein.
Huang
Gengming
G
Department of Pharmacology and Toxicology, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX, USA.
Elferink
Cornelis J
CJ
D000818:Animals; D001483:Base Sequence; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology*; D017931:DNA Primers; D004261:DNA Replication / Q000187:drug effects; D005786:Gene Expression Regulation; D005822:Genetic Vectors; D022781:Hepatocytes / Q000187:drug effects / Q000502:physiology; D008969:Molecular Sequence Data; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D018336:Receptors, Aryl Hydrocarbon / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000378:metabolism
D017931:DNA Primers; D000072317:Polychlorinated Dibenzodioxins; D034741:RNA, Small Interfering; D018336:Receptors, Aryl Hydrocarbon; D011993:Recombinant Fusion Proteins