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

Abstract

1,4-Bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP), an agonist of constitutive androstane receptor (CAR), is a well-known strong primary chemical mitogen for the mouse liver. Despite extensive investigation of the role of CAR in the regulation of cell proliferation, our knowledge of the intricate mediating mechanism is incomplete. In this study, we demonstrated that long-term CAR activation by TCPOBOP increased liver-to-body weight ratio and decreased tumour suppressor Foxo1 expression and transcriptional activity, which were correlated with reduced expression of genes regulated by Foxo1, including the cell-cycle inhibitor Cdkn1a(p21), and upregulation of the cell-cycle regulator Cyclin D1. Moreover, we demonstrated the negative regulatory effect of TCPOBOP-activated CAR on the association of Foxo1 with the target Foxo1 itself and Cdkn1a(p21) promoters. Thus, we identified CAR-mediated repression of cell cycle inhibitor p21, as mediated by repression of FOXO1 expression and transcriptional activity. CAR-FOXO1 cross-talk may provide new opportunities for understanding liver diseases and developing more effective therapeutic approaches to better drug treatments.

• Authors: Yuliya A Kazantseva, Andrei A Yarushkin, Vladimir O Pustylnyak
• Journal: Toxicology (Toxicology) Vol. 321 Pg. 73-9 (Jul 03 2014) ISSN: 1879-3185 [Electronic] Ireland
• PMID: 24769335 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Constitutive Androstane Receptor
• Cyclin-Dependent Kinase Inhibitor p21
• DNA, Complementary
• Forkhead Box Protein O1
• Forkhead Transcription Factors
• Foxo1 protein, mouse
• Pyridines
• RNA, Messenger
• Receptors, Cytoplasmic and Nuclear
• 1,4-bis(2-(3,5-dichloropyridyloxy))benzene
• Steroid Hydroxylases
• Aryl Hydrocarbon Hydroxylases
• Cyp2b10 protein, mouse
• Cytochrome P450 Family 2

Topics

• Animals
• Aryl Hydrocarbon Hydroxylases (metabolism)
• Blotting, Western
• Body Weight (drug effects)
• Chromatin Immunoprecipitation
• Constitutive Androstane Receptor
• Cyclin-Dependent Kinase Inhibitor p21 (genetics)
• Cytochrome P450 Family 2
• DNA, Complementary (biosynthesis, genetics)
• Forkhead Box Protein O1
• Forkhead Transcription Factors (genetics, physiology)
• Liver (enzymology, metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Microsomes, Liver (drug effects, enzymology)
• Mitosis (drug effects, genetics)
• Organ Size (drug effects)
• Pyridines (pharmacology)
• RNA, Messenger (biosynthesis, genetics)
• Real-Time Polymerase Chain Reaction
• Receptors, Cytoplasmic and Nuclear (antagonists & inhibitors, genetics, physiology)
• Steroid Hydroxylases (metabolism)