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Article
The Activated Aryl Hydrocarbon Receptor Synergizes Mitogen-Induced Murine Liver Hyperplasia
Toxicology
  • Kristen A. Mitchell, Boise State University
  • Shelly R. Wilson, University of Texas Medical Branch
  • Cornelis J. Elferink, University of Texas Medical Branch
Document Type
Article
Publication Date
10-1-2010
Disciplines
Abstract
Mechanisms of hepatocyte proliferation triggered by tissue loss are distinguishable from those that promote proliferation in the intact liver in response to mitogens. Previous studies demonstrate that exogenous activation of the aryl hydrocarbon receptor (AhR), a soluble ligand-activated transcription factor in the basic helix–loop–helix family of proteins, suppresses compensatory liver regeneration elicited by surgical partial hepatectomy. The goal of the present study was to determine how AhR activation modulates hepatocyte cell cycle progression in the intact liver following treatment with the hepatomitogen, 1,4-bis[2-(3,5-dichloropyridyloxy)] benzene (TCPOBOP). Mice were pretreated with the exogenous AhR agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) 24 h prior to treatment with TCPOBOP (3 mg/kg).). In contrast to the suppressive effects of AhR activation observed during compensatory regeneration, TCDD pretreatment resulted in a 30–50% increase in hepatocyte proliferation in the intact liver of TCPOBOP-treated mice. Although pretreatment with TCDD suppressed CDK2 kinase activity and increased the association of CDK2 with negative regulatory proteins p21Cip1 and p27Kip1, a corresponding increase in CDK4/cyclin D1 association and CDK4 activity which culminated in enhanced phosphorylation of retinoblastoma protein, consistent with the increased proliferative response. These findings are in stark contrast to previous observations that the activated AhR can suppress hepatocyte proliferation in vivo and reveal a new complexity to AhR-mediated cell cycle control.
Citation Information
Kristen A. Mitchell, Shelly R. Wilson and Cornelis J. Elferink. "The Activated Aryl Hydrocarbon Receptor Synergizes Mitogen-Induced Murine Liver Hyperplasia" Toxicology (2010)
Available at: http://works.bepress.com/kristen_mitchell/33/