Document Detail


Early growth response (EGR)-1 is required for timely cell-cycle entry and progression in hepatocytes after acute carbon tetrachloride exposure in mice.
MedLine Citation:
PMID:  21415413     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Cell-cycle induction in hepatocytes protects from prolonged tissue damage after toxic liver injury. Early growth response (Egr)-1(-/-) mice exhibit increased liver injury after carbon tetrachloride (CCl(4)) exposure and reduced TNF-α production. Because TNF-α is required for prompt cell-cycle induction after liver injury, here, we tested the hypothesis that Egr-1 is required for timely hepatocyte entry into the cell cycle after CCl(4)-induced liver injury. Acute liver injury was induced by a single injection of CCl(4). Assays were employed to assess indices of the cell cycle in liver after CCl(4) exposure. Bromodeoxyuridine incorporation peaked in wild-type mice at 48 h after CCl(4) but was reduced by 80% in Egr-1(-/-) mice. Proliferating-cell nuclear-antigen immunohistochemistry revealed blocks in cell-cycle entry and progression to DNA synthesis in Egr-1-deficient mice 48 h after CCl(4). Cyclin D, important for G0/G1 progression, was reduced at baseline and 36 h after CCl(4). Cyclin E1, required for G1/S-phase transition, was reduced in Egr-1(-/-) mice 24 and 48 h after CCl(4) exposure and was associated with reduced phosphorylation of the retinoblastoma protein. Proliferation in Egr-1(-/-) mice was delayed, rather than blocked, because indices of cell-cycle progression were restored 72 h after CCl(4) exposure. We concluded that Egr-1 was required for prompt cell-cycle entry (G0- to G1-phase) and G1/S-phase transition after toxic liver injury. These data support the hypothesis that Egr-1 provides hepatoprotection in the CCl(4)-injured liver, attributable, in part, to timely cell-cycle induction and progression.
Authors:
Michele T Pritchard; Robert N Malinak; Laura E Nagy
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2011-03-17
Journal Detail:
Title:  American journal of physiology. Gastrointestinal and liver physiology     Volume:  300     ISSN:  1522-1547     ISO Abbreviation:  Am. J. Physiol. Gastrointest. Liver Physiol.     Publication Date:  2011 Jun 
Date Detail:
Created Date:  2011-06-02     Completed Date:  2011-08-17     Revised Date:  2013-06-30    
Medline Journal Info:
Nlm Unique ID:  100901227     Medline TA:  Am J Physiol Gastrointest Liver Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  G1124-31     Citation Subset:  IM    
Affiliation:
Department of Pathobiology, Cleveland Clinic, Case Western Reserve University, Ohio 44106, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Carbon Tetrachloride
Cell Cycle*
Cell Proliferation*
Cyclin D / metabolism
Cyclin E / metabolism
Cytoprotection
DNA Replication
Disease Models, Animal
Drug-Induced Liver Injury / etiology,  genetics,  metabolism*,  pathology
Early Growth Response Protein 1 / deficiency,  genetics,  metabolism*
Hepatocytes / metabolism*,  pathology
Immunohistochemistry
Least-Squares Analysis
Linear Models
Liver Regeneration*
Mice
Mice, Inbred C57BL
Mice, Knockout
Phosphorylation
Proliferating Cell Nuclear Antigen / metabolism
Retinoblastoma Protein / metabolism
Time Factors
Grant Support
ID/Acronym/Agency:
F32 AA015833/AA/NIAAA NIH HHS; K99/R00 AA017918/AA/NIAAA NIH HHS; P20 AA17069/AA/NIAAA NIH HHS; R01 AA011975/AA/NIAAA NIH HHS
Chemical
Reg. No./Substance:
0/Cyclin D; 0/Cyclin E; 0/Early Growth Response Protein 1; 0/Egr1 protein, mouse; 0/Proliferating Cell Nuclear Antigen; 0/Retinoblastoma Protein; 56-23-5/Carbon Tetrachloride
Comments/Corrections

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