| Aryl hydrocarbon receptor regulates cell cycle progression in human breast cancer cells via a functional interaction with cyclin-dependent kinase 4. | |
MedLine Citation:
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PMID: 19917880 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor with constitutive activities and those induced by xenobiotic ligands, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). One unexplained cellular role for the AHR is its ability to promote cell cycle progression in the absence of exogenous ligands, whereas treatment with exogenous ligands induces cell cycle arrest. Within the cell cycle, progression from G(1) to S phase is controlled by sequential phosphorylation of the retinoblastoma protein (RB1) by cyclin D-cyclin-dependent kinase (CDK) 4/6 complexes. In this study, the functional interactions between the AHR, CDK4, and cyclin D1 (CCND1) were investigated as a potential mechanism for the cell cycle regulation by the AHR. Time course cell cycle and molecular experiments were performed in human breast cancer cells. The results demonstrated that the AHR and CDK4 interact within the cell cycle, and the interaction was disrupted upon TCDD treatment. The disruption was temporally correlated with G(1) cell cycle arrest and decreased phosphorylation of RB1. Biochemical reconstitution assays using in vitro-translated protein recapitulated the AHR and CDK4 interaction and showed that CCND1 was also part of the complex. In vitro assays for CDK4 kinase activity demonstrated that RB1 phosphorylation by the AHR/CDK4/CCND1 complex was reduced in the presence of TCDD. The results suggest that the AHR interacts in a complex with CDK4 and CCND1 in the absence of exogenous ligands to facilitate cell cycle progression. This interaction is disrupted by exogenous ligands, such as TCDD, to induce G(1) cell cycle arrest. |
Authors:
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Melissa A Barhoover; Julie M Hall; William F Greenlee; Russell S Thomas |
Publication Detail:
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Type: Comparative Study; Journal Article; Research Support, Non-U.S. Gov't Date: 2009-11-16 |
Journal Detail:
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Title: Molecular pharmacology Volume: 77 ISSN: 1521-0111 ISO Abbreviation: Mol. Pharmacol. Publication Date: 2010 Feb |
Date Detail:
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Created Date: 2010-01-20 Completed Date: 2010-02-11 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0035623 Medline TA: Mol Pharmacol Country: United States |
Other Details:
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Languages: eng Pagination: 195-201 Citation Subset: IM |
Affiliation:
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The Hamner Institutes for Health Sciences, Research Triangle Park, NC 27709, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Breast Neoplasms
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metabolism*,
pathology* Cell Cycle / drug effects, physiology* Cell Line, Tumor Cyclin-Dependent Kinase 4 / physiology* Female Humans Protein Binding / drug effects, physiology Receptors, Aryl Hydrocarbon / physiology* Tetrachlorodibenzodioxin / pharmacology |
| Chemical | |
Reg. No./Substance:
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0/Receptors, Aryl Hydrocarbon; 1746-01-6/Tetrachlorodibenzodioxin; EC 2.7.1.37/CDK4 protein, human; EC 2.7.11.22/Cyclin-Dependent Kinase 4 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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