CAR-mediated repression of Cdkn1a(p21) is accompanied by the Akt activation

Andrei A Yarushkin; Mark E Mazin; Anastasia Y Yunusova; Kseniya V Korchagina; Yuliya A Pustylnyak; Elena A Prokopyeva; Vladimir O Pustylnyak

doi:10.1016/j.bbrc.2018.06.032

CAR-mediated repression of Cdkn1a(p21) is accompanied by the Akt activation

Biochem Biophys Res Commun. 2018 Oct 2;504(2):361-366. doi: 10.1016/j.bbrc.2018.06.032. Epub 2018 Jun 11.

Authors

Andrei A Yarushkin¹, Mark E Mazin², Anastasia Y Yunusova³, Kseniya V Korchagina³, Yuliya A Pustylnyak², Elena A Prokopyeva¹, Vladimir O Pustylnyak⁴

Affiliations

¹ Novosibirsk State University, Novosibirsk, Pirogova Street, 1, 630090, Russia; Federal Research Center of Fundamental and Translational Medicine, Novosibirsk, Timakova Street, 2/12, 630117, Russia.
² Novosibirsk State University, Novosibirsk, Pirogova Street, 1, 630090, Russia.
³ Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, 8 Lavrentjev Avenue, 630090, Russia.
⁴ Novosibirsk State University, Novosibirsk, Pirogova Street, 1, 630090, Russia; Federal Research Center of Fundamental and Translational Medicine, Novosibirsk, Timakova Street, 2/12, 630117, Russia. Electronic address: pustylnyak@post.nsu.ru.

PMID: 29890134
DOI: 10.1016/j.bbrc.2018.06.032

Abstract

It was shown that CAR participates in the regulation of many cell processes. Thus, the activation of CAR causes a proliferating effect in the liver, which provides grounds to consider CAR as a therapeutic target when having a partial resection of this organ. Even though a lot of work has been done on the function of CAR in regulating hepatocyte proliferation, very little has been done on its complex mediating mechanism. This study, therefore, showed that the liver growth resulting from CAR activation leads to the decline in the level of PTEN protein and subsequent Akt activation in mouse liver. The increase of Akt activation produced by CAR agonist was accompanied by a decrease in the level of Foxo1, which was correlated with decreased expression of Foxo1 target genes, including Cdkn1a(p21). Moreover, the study also demonstrated that there exists a negative regulatory impact of CAR on the relationship between Foxo1 and targeted Cdkn1a(p21) promoter. Therefore, the study results revealed an essential function of CAR-Akt-Foxo1 signalling pathway in controlling hepatocyte proliferation by repressing the cell cycle regulator Cdkn1a (p21).

Keywords: Akt; Cdkn1a(p21); Constitutive androstane receptor; Liver; PTEN; TCPOBOP.

Publication types

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

MeSH terms

Animals
Apoptosis
Cell Proliferation
Constitutive Androstane Receptor
Cyclin-Dependent Kinase Inhibitor p21 / metabolism*
Forkhead Box Protein O1 / metabolism
Hepatocytes / cytology
Hepatocytes / metabolism*
Liver / metabolism
Male
Mice
Mice, Inbred C57BL
Promoter Regions, Genetic
Proto-Oncogene Proteins c-akt / metabolism*
Receptors, Cytoplasmic and Nuclear / metabolism*
Signal Transduction

Substances

Cdkn1a protein, mouse
Constitutive Androstane Receptor
Cyclin-Dependent Kinase Inhibitor p21
Forkhead Box Protein O1
Foxo1 protein, mouse
Receptors, Cytoplasmic and Nuclear
Akt1 protein, mouse
Proto-Oncogene Proteins c-akt