title: Growth suppression of Leydig TM3 cells mediated by aryl hydrocarbon receptor.
abstract: Exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin induces developmental toxicity in reproductive organs. To elucidate the function of AhR, we generated stable transformants of TM3 cells overexpressing wild-type aryl hydrocarbon receptor (AhR) or its mutants which carried mutations in nuclear localization signal or nuclear export signal. In the presence of 3-methylcholanthrene (MC), proliferation of the cells transfected with wild-type AhR was completely suppressed, whereas cells expressing AhR mutants proliferated in a manner equivalent to control TM3 cells, suggesting AhR-dependent growth inhibition. The suppression was associated with up-regulation of cyclin-dependent kinase inhibitor p21Cip1, which was abolished by pretreatment with actinomycin D. A p38 MAPK specific inhibitor, SB203580, blocked the increase of p21Cip1 mRNA in response to MC. Treatment with indigo, another AhR ligand, failed to increase of p21Cip1 mRNA, although up-regulation of mRNA for CYP1A1 was observed. These data suggest AhR in Leydig cells mediates growth inhibition by inducing p21Cip1.
authors.affiliation: Research Institute for Clinical Oncology, Saitama Cancer Center, Saitama, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Iseki
authors.forename: Togo
authors.initials: T
authors.lastname: Ikuta
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Kaname
authors.initials: K
authors.lastname: Kawajiri
mesh_terms: D000818:Animals; D001483:Base Sequence; D018797:Cell Cycle Proteins / Q000096:biosynthesis / Q000378:metabolism; D002455:Cell Division / Q000502:physiology*; D002460:Cell Line; D050759:Cyclin-Dependent Kinase Inhibitor p21; D017931:DNA Primers; D007985:Leydig Cells / Q000166:cytology* / Q000201:enzymology; D008297:Male; D051379:Mice; D016297:Mutagenesis, Site-Directed; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000502:physiology*
chemical_list: C493957:Cdkn1a protein, mouse; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D017931:DNA Primers; D018336:Receptors, Aryl Hydrocarbon