TY - JOUR

T1 - CAR-mediated repression of Cdkn1a(p21) is accompanied by the Akt activation

AU - Yarushkin, Andrei A.

AU - Mazin, Mark E.

AU - Yunusova, Anastasia Y.

AU - Korchagina, Kseniya V.

AU - Pustylnyak, Yuliya A.

AU - Prokopyeva, Elena A.

AU - Pustylnyak, Vladimir O.

N1 - Publisher Copyright: © 2018 Elsevier Inc.

PY - 2018/10/2

Y1 - 2018/10/2

N2 - 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).

AB - 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).

KW - Akt

KW - Cdkn1a(p21)

KW - Constitutive androstane receptor

KW - Liver

KW - PTEN

KW - TCPOBOP

KW - FORKHEAD TRANSCRIPTION FACTOR

KW - MOUSE LIVERS

KW - HEPATECTOMY

KW - C-MYC

KW - FOXO1

KW - CONSTITUTIVE ANDROSTANE RECEPTOR

KW - LIVER-REGENERATION

KW - FACTOR FKHR

KW - CELL-CYCLE

KW - EXPRESSION

KW - Cell Proliferation

KW - Forkhead Box Protein O1/metabolism

KW - Male

KW - Proto-Oncogene Proteins c-akt/metabolism

KW - Liver/metabolism

KW - Cyclin-Dependent Kinase Inhibitor p21/metabolism

KW - Promoter Regions, Genetic

KW - Signal Transduction

KW - Mice, Inbred C57BL

KW - Receptors, Cytoplasmic and Nuclear/metabolism

KW - Animals

KW - Hepatocytes/cytology

KW - Mice

KW - Apoptosis

UR - http://www.scopus.com/inward/record.url?scp=85048221931&partnerID=8YFLogxK

U2 - 10.1016/j.bbrc.2018.06.032

DO - 10.1016/j.bbrc.2018.06.032

M3 - Article

C2 - 29890134

AN - SCOPUS:85048221931

VL - 504

SP - 361

EP - 366

JO - Biochemical and Biophysical Research Communications

JF - Biochemical and Biophysical Research Communications

SN - 0006-291X

IS - 2

ER -