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

Yuliya A Kazantseva; Andrei A Yarushkin; Vladimir O Pustylnyak

doi:10.1016/j.tox.2014.04.003

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

Toxicology. 2014 Jul 3:321:73-9. doi: 10.1016/j.tox.2014.04.003. Epub 2014 Apr 24.

Authors

Yuliya A Kazantseva¹, Andrei A Yarushkin¹, Vladimir O Pustylnyak²

Affiliations

¹ Institute of Molecular Biology and Biophysics SB RAMS, Timakova str. 2, Novosibirsk 630117, Russia.
² Institute of Molecular Biology and Biophysics SB RAMS, Timakova str. 2, Novosibirsk 630117, Russia; Novosibirsk State University, Pirogova str. 2, Novosibirsk 630090, Russia. Electronic address: pustylnyak@ngs.ru.

PMID: 24769335
DOI: 10.1016/j.tox.2014.04.003

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.

Keywords: Cell cycle; Constitutive androstane receptor; FOXO1; Liver; Mitogen; TCPOBOP.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

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
DNA, Complementary / genetics
Forkhead Box Protein O1
Forkhead Transcription Factors / genetics*
Forkhead Transcription Factors / physiology*
Liver / enzymology
Liver / metabolism*
Male
Mice
Mice, Inbred C57BL
Microsomes, Liver / drug effects
Microsomes, Liver / enzymology
Mitosis / drug effects
Mitosis / genetics
Organ Size / drug effects
Pyridines / pharmacology
RNA, Messenger / biosynthesis
RNA, Messenger / genetics
Real-Time Polymerase Chain Reaction
Receptors, Cytoplasmic and Nuclear / antagonists & inhibitors
Receptors, Cytoplasmic and Nuclear / genetics*
Receptors, Cytoplasmic and Nuclear / physiology*
Steroid Hydroxylases / metabolism

Substances

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