The activated aryl hydrocarbon receptor synergizes mitogen-induced murine liver hyperplasia

Kristen A. Mitchell, Shelly R. Wilson, Cornelis Elferink

Research output: Contribution to journalArticle

10 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)103-109
Number of pages7
JournalToxicology
Volume276
Issue number2
DOIs
StatePublished - Oct 2010

Fingerprint

Aryl Hydrocarbon Receptors
Mitogens
Liver
Hyperplasia
Hepatocytes
Chemical activation
Cells
Association reactions
Cyclin-Dependent Kinase Inhibitor p27
Basic Helix-Loop-Helix Transcription Factors
Retinoblastoma Protein
Phosphorylation
Liver Regeneration
Cyclin D1
Hepatectomy
Cell Cycle Checkpoints
Regeneration
Cell Cycle
Proteins
Transcription Factors

Keywords

  • AhR
  • Hyperplasia
  • Liver
  • TCDD
  • TCPOBOP

ASJC Scopus subject areas

  • Toxicology
  • Medicine(all)

Cite this

The activated aryl hydrocarbon receptor synergizes mitogen-induced murine liver hyperplasia. / Mitchell, Kristen A.; Wilson, Shelly R.; Elferink, Cornelis.

In: Toxicology, Vol. 276, No. 2, 10.2010, p. 103-109.

Research output: Contribution to journalArticle

Mitchell, Kristen A. ; Wilson, Shelly R. ; Elferink, Cornelis. / The activated aryl hydrocarbon receptor synergizes mitogen-induced murine liver hyperplasia. In: Toxicology. 2010 ; Vol. 276, No. 2. pp. 103-109.
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