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Ah receptor-mediated suppression of liver regeneration through NC-XRE-driven p21Cip1 expression

Daniel P Jackson1, Hui Li, Kristen A Mitchell

  • 1Department of Pharmacology and Toxicology (D.P.J., A.D.J., C.J.E.) and Department of Pediatrics (H.L.), University of Texas Medical Branch, Galveston, Texas; and Department of Biological Sciences, Boise State University, Boise, Idaho (K.A.M.).

Molecular Pharmacology
|January 17, 2014
PubMed

Insights

The aryl hydrocarbon receptor (AhR) agonist TCDD inhibits liver regeneration by increasing p21(Cip1) expression, which halts cell cycle progression. This inhibition is completely abolished in mice lacking p21(Cip1).

Area of Science:

  • Hepatology
  • Molecular Biology
  • Toxicology

Background:

  • The aryl hydrocarbon receptor (AhR) is known to disrupt G1 cell cycle progression in hepatocytes upon exposure to persistent agonists like TCDD.
  • This growth arrest is linked to the inhibition of cyclin-dependent kinase 2 (CDK2) activity.

Purpose of the Study:

  • To investigate the role of p21(Cip1) and p27(Kip1) in TCDD-induced inhibition of liver regeneration following partial hepatectomy.
  • To elucidate the mechanism by which TCDD affects liver regeneration in the absence of these key cell cycle inhibitors.

Main Methods:

  • Partial hepatectomy was performed on wild-type, p21(Cip1) knockout, and p27(Kip1) knockout mice.
  • Mice were exposed to TCDD, and liver regeneration was assessed.
  • Transcriptional responses and AhR binding to DNA were analyzed using chromatin immunoprecipitation.

Main Results:

  • TCDD-induced inhibition of liver regeneration was entirely dependent on p21(Cip1) expression.
  • Hepatocyte progression through G1 phase during regeneration was accelerated in p21(Cip1) knockout mice compared to wild-type.
  • Increased p21(Cip1) expression during regeneration involved an AhR-dependent mechanism, requiring AhR binding to a novel xenobiotic response element with Kruppel-like factor 6.

Conclusions:

  • Liver regeneration inhibition by TCDD is mediated through an AhR-dependent induction of p21(Cip1).
  • AhR functionality during liver regeneration is linked to p21(Cip1)-regulated signaling, connecting AhR biology to the G1 cell cycle program.

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