NDLI: Diurnal Regulation of the Early Growth Response 1 (Egr-1) Protein Expression by Hepatocyte Nuclear Factor 4α (HNF4α) and Small Heterodimer Partner (SHP) Cross-talk in Liver Fibrosis

Content Provider	Journal of Biological Chemistry (JBC)
Author	Zhang, Yuxia Bonzo, Jessica A. Gonzalez, Frank J. Wang, Li
Abstract	Early growth response 1 (Egr-1) protein is a critical regulator of genes contributing to liver fibrosis; however, little is known about the upstream transcriptional factors that control its expression. Here we show that Egr-1 expression is tightly regulated by nuclear receptor signaling. Hepatocyte nuclear factor 4α (HNF4α) activated the Egr-1 promoter through three DR1 response elements as identified by trans-activation assays. Deletion of these response elements or knockdown of HNF4α using siRNA largely abrogated Egr-1 promoter activation. HNF4α activity, as well as its enrichment on the Egr-1 promoter, were markedly repressed by small heterodimer partner (SHP) co-expression. Egr-1 mRNA and protein were transiently induced by HNF4α. On the contrary, HNF4α siRNA reduced Egr-1 expression at both the mRNA and protein levels, and overexpression of SHP reversed these effects. Conversely, knockdown of SHP by siRNA elevated Egr-1 protein. Interestingly, Egr-1 mRNA exhibited diurnal fluctuation, which was synchronized to the cyclic expression of SHP and HNF4α after cells were released from serum shock. Unexpectedly, the levels of Egr-1 mRNA and protein were highly up-regulated in Hnf4α−/− mice. Both HNF4α and Egr-1 expression were dramatically increased in SHP−/− mice with bile duct ligation and in human cirrhotic livers, which was inversely correlated with diminished SHP expression. In conclusion, our study revealed control network for Egr-1 expression through a feedback loop between SHP and HNF4α.
Related Links	http://www.jbc.org/content/286/34/29635.abstract
Ending Page	29643
Starting Page	29635
Page Count	9
File Format	HTM / HTML PDF
ISSN	00219258
Journal	Journal of Biological Chemistry (JBC)
Issue Number	34
Volume Number	286
DOI	10.1074/jbc.M111.253039
e-ISSN	1083351X
Language	English
Publisher	American Society for Biochemistry and Molecular Biology
Publisher Date	2011-08-26
Access Restriction	Open
Subject Keyword	Gene Knockout Gene Regulation Liver Injury Nuclear Receptors Transcription Factors Transcription Promoter Transcription Regulation Molecular Bases of Disease
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

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Diurnal Regulation of the Early Growth Response 1 (Egr-1) Protein Expression by Hepatocyte Nuclear Factor 4α (HNF4α) and Small Heterodimer Partner (SHP) Cross-talk in Liver Fibrosis*

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