title: 2,3,7,8-Tetrachlorodibenzo-p-dioxin inhibits cell proliferation through arylhydrocarbon receptor-mediated G1 arrest in SK-N-SH human neuronal cells.
abstract: The neurotoxic mechanism of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has not been completely elucidated. In this study we investigated the possible role of cell cycle regulators and their dependence on arylhydrocarbon receptor (AhR) in the TCDD-mediated inhibition of cell proliferation using a human neuronal cell system. TCDD suppressed DNA synthesis of SK-N-SH human neuronal cells determined by [(3)H]thymidine incorporation which was significantly prevented either by pretreatment with alpha-naphthoflavone (alpha-NF), a partial AhR antagonist, or 8-methoxypsoralen (MOP), a binding inhibitor of activated AhR to dioxin response elements. Cell cycle analysis showed that TCDD induced a G(1) cell cycle arrest, which was also significantly prevented by pretreatment with alpha-NF and MOP. TCDD did not alter the expression of cyclin D, cyclin E, p21 and p53. However, TCDD induced an enhanced expression of p27 and a hypophosphorylation of pRb, which was prevented by alpha-NF and MOP. Combined, these results suggest that the TCDD-induced inhibition of neuronal cell proliferation may be due to the AhR-dependent G(1) arrest through an enhanced expression of p27 and a hypophosphorylation of pRB.
authors.affiliation: College of Pharmacy, Yeungnam University, Gyongsan 712-749, South Korea.
authors.forename: Da-Qing
authors.initials: DQ
authors.lastname: Jin
authors.forename: Jae Wook
authors.initials: JW
authors.lastname: Jung
authors.forename: Yong Soo
authors.initials: YS
authors.lastname: Lee
authors.forename: Jung-Ae
authors.initials: JA
authors.lastname: Kim
mesh_terms: D017500:Adenovirus E1A Proteins; D001571:Benzoflavones / Q000494:pharmacology; D015153:Blotting, Western / Q000379:methods; D002352:Carrier Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D004347:Drug Interactions; D005434:Flow Cytometry / Q000379:methods; D016193:G1 Phase / Q000187:drug effects*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D008730:Methoxsalen / Q000494:pharmacology; D009447:Neuroblastoma; D009687:Nuclear Proteins; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology*; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis; D018336:Receptors, Aryl Hydrocarbon / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012097:Repressor Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013723:Teratogens / Q000494:pharmacology*; D013936:Thymidine / Q000493:pharmacokinetics; D013997:Time Factors; D014316:Tritium / Q000493:pharmacokinetics
chemical_list: D017500:Adenovirus E1A Proteins; D001571:Benzoflavones; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C416925:EID1 protein, human; D009687:Nuclear Proteins; D000072317:Polychlorinated Dibenzodioxins; D018809:Proliferating Cell Nuclear Antigen; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D012097:Repressor Proteins; D013723:Teratogens; C413374:p27 antigen; D014316:Tritium; C011512:alpha-naphthoflavone; D008730:Methoxsalen; D013936:Thymidine