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E2F1 is a potential novel regulator of liver fibrosis by targeting Egr‐1 through nuclear receptor SHP
Author(s) -
zhang yuxia,
wang li
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.1153.1
Subject(s) - fibrosis , e2f1 , transcription factor , small heterodimer partner , cancer research , regulator , luciferase , hepatic stellate cell , chemistry , hepatocyte , nuclear receptor , biology , microbiology and biotechnology , endocrinology , medicine , transfection , gene , in vitro , biochemistry
Objective Egr‐1 is a critical regulator of liver fibrosis. However, the transcriptional network that governs Egr‐1 expression remains largely unknown. This study aimed at identifying novel transcriptional factors controlling Egr‐1 expression and liver fibrosis. Methods Luciferase reporter and ChIP assays were used to elucidate the mechanisms. Mouse models of liver fibrosis induced by bile‐duct ligation (BDL), CCl4, or 3,5‐diethoxycarbonyl‐1,4‐dihydrocollidine were used as in vivo models. Results The SHP‐/‐ mice showed increased fibrosis in response to BDL, which was reversed in hepatocyte SHP‐overexpressed mice. The Egr‐1 promoter was activated by E2F1, and the activation was abrogated by co‐expression of SHP and EID1 in both human hepatoma Huh7 and stellate cells LX2. ChIP assays confirmed the association of E2F1 and SHP with the Egr‐1 promoter, and GST pull‐down confirmed a direct interaction between E2F1 and SHP. Interestingly, the loss of E2F1 had no effect in CCl4‐intoxicated mice, but significantly decreased liver fibrosis of the biliary type. Importantly, E2F1 and Egr‐1 expression were dramatically increased in human cirrhotic liver, which was inversely correlated with diminished SHP expression. Conclusions Egr‐1 expression is regulated by a transcription network involving E2F1 and SHP. E2F1 may function as a novel fibrogenic gene. Supported by T32CA092347 (Y.Z) and DK080440 (L.W).