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Molecular Pharmacology

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Research ArticleArticle

Aryl Hydrocarbon Receptor Regulates Cell Cycle Progression in Human Breast Cancer Cells via a Functional Interaction with Cyclin-Dependent Kinase 4

Melissa A. Barhoover, Julie M. Hall, William F. Greenlee and Russell S. Thomas
Molecular Pharmacology February 2010, 77 (2) 195-201; DOI: https://doi.org/10.1124/mol.109.059675
Melissa A. Barhoover
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Julie M. Hall
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William F. Greenlee
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Russell S. Thomas
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Abstract

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 G1 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 G1 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 G1 cell cycle arrest.

Footnotes

  • This work was supported by The Hamner Pilot Projects Initiative, The Hamner Institutes for Health Sciences.

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    doi:10.1124/mol.109.059675.

  • ABBREVIATIONS:

    AHR
    aryl hydrocarbon receptor
    ARNT
    aryl hydrocarbon nuclear translocator
    CDK4
    cyclin-dependent kinase 4
    ER−
    estrogen receptor negative
    ER+
    estrogen receptor positive
    TCDD
    2,3,7,8-tetrachlorodibenzo-p-dioxin
    RB1
    retinoblastoma protein
    CCND1
    cyclin D1
    FBS
    fetal bovine serum
    C/D FBS
    charcoal-stripped fetal bovine serum
    E2
    17-β-estradiol
    HSP90
    90-kDa heat shock protein
    DMSO
    dimethyl sulfoxide
    DMEM
    Dulbecco's modified Eagle's medium
    PAGE
    polyacrylamide gel electrophoresis
    PVDF
    polyvinylidene difluoride
    PCR
    polymerase chain reaction
    IP
    immunoprecipitation
    ECL
    enhanced chemiluminescence
    MEM
    minimal essential medium.

  • Received July 22, 2009.
  • Accepted November 16, 2009.
  • Copyright © 2010 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 77 (2)
Molecular Pharmacology
Vol. 77, Issue 2
1 Feb 2010
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Research ArticleArticle

Aryl Hydrocarbon Receptor Regulates Cell Cycle Progression in Human Breast Cancer Cells via a Functional Interaction with Cyclin-Dependent Kinase 4

Melissa A. Barhoover, Julie M. Hall, William F. Greenlee and Russell S. Thomas
Molecular Pharmacology February 1, 2010, 77 (2) 195-201; DOI: https://doi.org/10.1124/mol.109.059675

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Research ArticleArticle

Aryl Hydrocarbon Receptor Regulates Cell Cycle Progression in Human Breast Cancer Cells via a Functional Interaction with Cyclin-Dependent Kinase 4

Melissa A. Barhoover, Julie M. Hall, William F. Greenlee and Russell S. Thomas
Molecular Pharmacology February 1, 2010, 77 (2) 195-201; DOI: https://doi.org/10.1124/mol.109.059675
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