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PMID: 10398686 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

p27(Kip1) induction and inhibition of proliferation by the intracellular Ah receptor in developing thymus and hepatoma cells.

Genes & development ·Vol. 13 ·No. 13 ·1999-07-01 ·Pages 1742-53

Kolluri SK, Weiss C, Koff A, Göttlicher M

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.

MeSH Terms
Animals Carcinoma, Hepatocellular/pathology Cell Cycle/drug effects,genetics Cell Cycle Proteins Cell Hypoxia/genetics Culture Media, Serum-Free Cyclin-Dependent Kinase Inhibitor p27 Drug Resistance Gene Expression Regulation, Developmental/drug effects Gene Expression Regulation, Neoplastic/drug effects Humans Liver Neoplasms/pathology Mice Mice, Knockout Microtubule-Associated Proteins/biosynthesis,deficiency,genetics,physiology Neoplasm Proteins/biosynthesis,genetics,physiology Phosphorylation/drug effects Polychlorinated Dibenzodioxins/metabolism,pharmacology,toxicity Protein Processing, Post-Translational/drug effects Receptors, Aryl Hydrocarbon/physiology Retinoblastoma Protein/metabolism Thymus Gland/cytology Transcription, Genetic Tumor Cells, Cultured Tumor Suppressor Proteins
Chemicals
Cdkn1b protein, mouse Cell Cycle Proteins Culture Media, Serum-Free Microtubule-Associated Proteins Neoplasm Proteins Polychlorinated Dibenzodioxins Receptors, Aryl Hydrocarbon Retinoblastoma Protein Tumor Suppressor Proteins Cyclin-Dependent Kinase Inhibitor p27
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Kolluri S K
Forschungszentrum Karlsruhe, Institute of Genetics, 76021 Karlsruhe, Germany.
Weiss C
Koff A
Göttlicher M
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Article Info
Journal
Genes & development
Abbr.
Genes Dev
ISSN
0890-9369
DOI
10.1101/gad.13.13.1742
Published
1999-07-01
Pages
1742-53
Language
English
Region
United States
NLM ID
8711660
PMCID
PMC316853
Subset
IM
External Links
PubMed source DOI: 10.1101/gad.13.13.1742 PMC Full Text View journal details
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