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Int J Biochem Cell Biol. 2015 Jul;64:147-54. doi: 10.1016/j.biocel.2015.04.003. Epub 2015 Apr 13.

Regulation of mice liver regeneration by early growth response-1 through the GGPPS/RAS/MAPK pathway.

Author information

1
Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University and Model Animal Research Center, National Resource Center for Mutant Mice, Nanjing, 210093, China.
2
Biochemical and Environmental Engineering School of Xiaozhuang Collage, Nanjing 211171, China.
3
Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University and Model Animal Research Center, National Resource Center for Mutant Mice, Nanjing, 210093, China; Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital, School of Medicine, Nanjing University, Nanjing 210093, China.
4
Jiangsu Key Laboratory for Molecular and Medical Biotechnology, Nanjing Normal University, Nanjing 210097, China.
5
Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital, School of Medicine, Nanjing University, Nanjing 210093, China.
6
Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, Massachusetts 02115, USA.
7
MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Center and the School of Medicine, Nanjing University, National Resource Center for Mutant Mice, Nanjing 210093, China.
8
Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University and Model Animal Research Center, National Resource Center for Mutant Mice, Nanjing, 210093, China. Electronic address: licj@nju.edu.cn.
9
Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University and Model Animal Research Center, National Resource Center for Mutant Mice, Nanjing, 210093, China. Electronic address: xuebin@nju.edu.cn.

Abstract

BACKGROUND & AIMS:

Liver regeneration (LR) consists of a series of complicated processes in which several transcription factors play important roles. Among them, the early growth response 1 gene (EGR-1) is rapidly induced in response to liver resection. Previous studies have shown that EGR-1-/- mice exhibit delayed hepatocellular mitotic progression after partial hepatectomy (PH). The mechanism underlying the EGR-1 regulated LR is still unknown. Our aim is to elucidate the underlying mechanism.

METHODS:

Mice infected with adenoviral vectors expressing GFP, EGR-1 or dominant negative EGR-1 (dnEGR-1) were subjected to 2/3 PH. The serum starvation recovery cell model was chosen to mimic the regeneration process for the in vitro studies. Cell proliferation and signaling pathways downstream of geranylgeranyl diphosphate synthase (GGPPS) were examined in the regenerating liver and serum starvation recovery cell model.

RESULTS:

Loss of function of EGR-1 significantly inhibited liver recovery and the expression of cyclin D1, cyclin E, and proliferating cell nuclear antigen (PCNA). The expression of GGPPS and the activity of the downstream RAS/MAPK pathway were inhibited in dnEGR-1-infected liver, which was consistent with the serum-induced cell model. In addition, loss of function of EGR-1 aggravated liver damage with increased serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels.

CONCLUSIONS:

EGR-1-induced GGPPS plays a vital role in the LR after PH through the RAS/MAPK signaling.

KEYWORDS:

EGR-1; GGPPS; Liver regeneration; MAPK; Serum starvation recovery

PMID:
25882493
DOI:
10.1016/j.biocel.2015.04.003
[Indexed for MEDLINE]

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