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CAR-mediated repression of Foxo1 transcriptional activity regulates the cell cycle inhibitor p21 in mouse livers

Yuliya A Kazantseva1, Andrei A Yarushkin1, Vladimir O Pustylnyak2

  • 1Institute of Molecular Biology and Biophysics SB RAMS, Timakova str. 2, Novosibirsk 630117, Russia.

Toxicology
|April 29, 2014
PubMed

Insights

Constitutive androstane receptor (CAR) activation by TCPOBOP promotes liver growth by reducing the expression and activity of the tumor suppressor Foxo1. This mechanism involves decreased expression of the cell cycle inhibitor p21, offering insights into liver disease therapies.

Area of Science:

  • Hepatology
  • Molecular Biology
  • Cellular Signaling

Background:

  • Constitutive androstane receptor (CAR) is a key regulator of liver function and cell proliferation.
  • TCPOBOP is a potent CAR agonist known to induce liver growth in mice.
  • The precise mechanisms by which CAR influences liver cell proliferation remain incompletely understood.

Purpose of the Study:

  • To elucidate the molecular mechanisms underlying CAR-mediated liver mitogenesis.
  • To investigate the role of Foxo1 in CAR-induced liver enlargement.
  • To identify novel cross-talk between CAR and cell cycle regulators.

Main Methods:

  • Long-term administration of TCPOBOP to mice.
  • Assessment of liver-to-body weight ratio.
  • Quantitative analysis of Foxo1, Cdkn1a (p21), and Cyclin D1 expression and transcriptional activity.
  • Chromatin immunoprecipitation assays to evaluate protein-DNA interactions.

Main Results:

  • TCPOBOP treatment significantly increased liver-to-body weight ratio.
  • CAR activation led to decreased Foxo1 expression and transcriptional activity.
  • Reduced expression of Foxo1-regulated genes, including the cell-cycle inhibitor Cdkn1a (p21), was observed.
  • Upregulation of the cell-cycle regulator Cyclin D1 occurred.
  • TCPOBOP-activated CAR negatively regulated the association of Foxo1 with its own promoter and the Cdkn1a (p21) promoter.

Conclusions:

  • CAR activation by TCPOBOP represses the cell cycle inhibitor p21 through the downregulation of Foxo1 expression and transcriptional activity.
  • CAR-FOXO1 cross-talk represents a critical pathway in liver growth regulation.
  • This pathway offers potential therapeutic targets for liver diseases and drug treatments.
Keywords:
Cell cycleConstitutive androstane receptorFOXO1LiverMitogenTCPOBOP

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