Abstract
The Ah receptor (AhR), a bHLH/PAS transcription factor, mediates dioxin toxicity in the immune system, skin, testis and liver. Toxic phenomena are associated with altered cell proliferation or differentiation, but signaling pathways of AhR in cell cycle regulation are poorly understood. Here we show that AhR induces the p27(Kip1) cyclin/cdk inhibitor by altering Kip1 transcription in a direct mode without the need for ongoing protein synthesis or cell proliferation. This is the first example of Kip1 being a direct transcriptional target of a toxic agent that affects cell proliferation. Kip1 causes dioxin-induced suppression of 5L hepatoma cell proliferation because Kip1 antisense-expressing cells are resistant to dioxins. Kip1 is also induced by dioxins in cultures of fetal thymus glands concomitant with inhibition of proliferation and severe reduction of thymocyte recovery. Kip1 expression is likely to mediate these effects as thymic glands of Kip1-deficient mice (Kip1(Delta51)) are largely, though not completely, resistant.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Carcinoma, Hepatocellular / pathology*
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Cell Cycle / drug effects*
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Cell Cycle / genetics
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Cell Cycle Proteins*
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Cell Hypoxia / genetics
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Culture Media, Serum-Free
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Cyclin-Dependent Kinase Inhibitor p27
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Drug Resistance
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Gene Expression Regulation, Developmental / drug effects*
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Gene Expression Regulation, Neoplastic / drug effects*
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Humans
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Liver Neoplasms / pathology*
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Mice
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Mice, Knockout
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Microtubule-Associated Proteins / biosynthesis
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Microtubule-Associated Proteins / deficiency
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Microtubule-Associated Proteins / genetics
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Microtubule-Associated Proteins / physiology*
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Neoplasm Proteins / biosynthesis
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Neoplasm Proteins / genetics
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Neoplasm Proteins / physiology
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Phosphorylation / drug effects
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Polychlorinated Dibenzodioxins / metabolism
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Polychlorinated Dibenzodioxins / pharmacology
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Polychlorinated Dibenzodioxins / toxicity*
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Protein Processing, Post-Translational / drug effects
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Receptors, Aryl Hydrocarbon / physiology*
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Retinoblastoma Protein / metabolism
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Thymus Gland / cytology*
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Transcription, Genetic
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Tumor Cells, Cultured
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Tumor Suppressor Proteins*
Substances
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Cdkn1b protein, mouse
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Cell Cycle Proteins
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Culture Media, Serum-Free
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Microtubule-Associated Proteins
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Neoplasm Proteins
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Polychlorinated Dibenzodioxins
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Receptors, Aryl Hydrocarbon
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Retinoblastoma Protein
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Tumor Suppressor Proteins
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Cyclin-Dependent Kinase Inhibitor p27