| 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(Δ51)) are largely, though not completely, resistant. |
| Keywords: |
controlled study; nonhuman; carcinoma, hepatocellular; liver neoplasms; cell proliferation; animal cell; mouse; animals; cell cycle proteins; mice; mice, knockout; animal tissue; cell cycle; embryo; neoplasm proteins; transcription factor; genetic transcription; transcription, genetic; drug resistance; tumor cells, cultured; phosphorylation; animalia; gene expression regulation, developmental; gene expression regulation, neoplastic; protein processing, post-translational; thymus; thymus gland; messenger rna; protein p27; cyclin-dependent kinase inhibitor p27; tumor suppressor proteins; cell hypoxia; fetus; cyclin dependent kinase inhibitor; retinoblastoma protein; aromatic hydrocarbon receptor; receptors, aryl hydrocarbon; microtubule-associated proteins; 2,3,7,8 tetrachlorodibenzo para dioxin; culture media, serum-free; hepatoma cell; dioxins; humans; priority journal; article; fetal thymus; tetrachlorodibenzodioxin; cyclin dependent kinase inhibitors; mrna induction; pas proteins; dioxin
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