Sustained aryl hydrocarbon receptor activity attenuates liver regeneration

Kristen A. Mitchell, Courtney A. Lockhart, Gengming Huang, Cornelis Elferink

Research output: Contribution to journalArticle

60 Citations (Scopus)

Abstract

In hepatocyte-derived cell lines, either loss of aryl hydrocarbon receptor (AhR) function or treatment with a persistent AhR agonist such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) can disrupt G1 phase cell cycle progression. The present study used liver regeneration to explore mechanistically how AhR activity modulates hepatocyte proliferation in vivo. Treatment of mice with 20 μg/kg TCDD 1 day before 70% partial hepatectomy (PH) resulted in a 50 to 75% suppression in liver regeneration. Impaired proliferation was not associated with changes in levels of interleukin-6 or tumor necrosis factor-α, which prime quiescent hepatocytes to enter G 1 phase. In fact, administration of TCDD 12 h after PH, a period well beyond the priming phase, still induced the G1 arrest. Decreased proliferation in TCDD-treated mice correlated with reduced cyclin-dependent kinase-2 (CDK2) activity, a pivotal regulator of G1/S phase transition. In contrast to observations made in cell culture, suppressed CDK2 activity was not strictly associated with increased binding of the CDK2 inhibitors p21Cip1 or p27Kip1. However, TCDD decreased levels of cyclin E binding to CDK2, despite normal cyclin E expression. The evidence also suggests that TCDD-induced hepatic growth arrest depends upon sustained AhR activity because transient AhR activation in response to endogenous queues failed to suppress the regenerative response. These findings establish a functional role for the AhR in regulating normal cell cycle control during liver regeneration.

Original languageEnglish (US)
Pages (from-to)163-170
Number of pages8
JournalMolecular Pharmacology
Volume70
Issue number1
DOIs
StatePublished - 2006

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Aryl Hydrocarbon Receptors
Liver Regeneration
Cyclin-Dependent Kinase 2
Hepatocytes
Cyclin E
G1 Phase
Hepatectomy
Phase Transition
Cell Cycle Checkpoints
S Phase
Polychlorinated Dibenzodioxins
Interleukin-6
Cell Cycle
Cell Culture Techniques
Tumor Necrosis Factor-alpha
Cell Line
Liver
Growth

ASJC Scopus subject areas

  • Pharmacology

Cite this

Sustained aryl hydrocarbon receptor activity attenuates liver regeneration. / Mitchell, Kristen A.; Lockhart, Courtney A.; Huang, Gengming; Elferink, Cornelis.

In: Molecular Pharmacology, Vol. 70, No. 1, 2006, p. 163-170.

Research output: Contribution to journalArticle

Mitchell, Kristen A. ; Lockhart, Courtney A. ; Huang, Gengming ; Elferink, Cornelis. / Sustained aryl hydrocarbon receptor activity attenuates liver regeneration. In: Molecular Pharmacology. 2006 ; Vol. 70, No. 1. pp. 163-170.
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