title: Early growth response (EGR)-1 is required for timely cell-cycle entry and progression in hepatocytes after acute carbon tetrachloride exposure in mice.
abstract: 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.affiliation: Department of Pathobiology, Cleveland Clinic, Case Western Reserve University, Ohio 44106, USA.
authors.forename: Michele T
authors.initials: MT
authors.lastname: Pritchard
authors.forename: Robert N
authors.initials: RN
authors.lastname: Malinak
authors.forename: Laura E
authors.initials: LE
authors.lastname: Nagy
mesh_terms: D000818:Animals; D002251:Carbon Tetrachloride; D002453:Cell Cycle; D049109:Cell Proliferation; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D056741:Cyclin D / Q000378:metabolism; D019927:Cyclin E / Q000378:metabolism; D019610:Cytoprotection; D004261:DNA Replication; D004195:Disease Models, Animal; D051766:Early Growth Response Protein 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism* / Q000473:pathology; D007150:Immunohistochemistry; D016018:Least-Squares Analysis; D016014:Linear Models; D008115:Liver Regeneration; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism; D013997:Time Factors
chemical_list: D056741:Cyclin D; D019927:Cyclin E; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D018809:Proliferating Cell Nuclear Antigen; D016160:Retinoblastoma Protein; D002251:Carbon Tetrachloride