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Regulation of the Transcription of the UbD Promoter and Identification of ISRE Sequence
Author(s) -
Oliva Joan,
BardagGorce Fawzia,
French Samuel W.
Publication year - 2010
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.24.1_supplement.456.10
Subject(s) - biology , reporter gene , microbiology and biotechnology , promoter , regulation of gene expression , transcriptional regulation , transcription (linguistics) , gene expression , transcription factor , cancer research , gene , response element , genetics , linguistics , philosophy
Mallory‐Denk bodies (MDBs) are found in the liver of patients with alcoholic and chronic nonalcoholic liver disease, and human hepatocellular carcinoma (HCC). DDC is used as a model to induce the formation of MDBs in mouse liver. Previous studies showed that DDC induced the expression of UbD. The mechanism of transcriptional regulation of the gene UbD is unknown, but previous publication showed that inflammatory cytokines played a key role. The understanding of this regulation is very important because UbD is a liver preneoplastic marker, over expressed in 70–90% of the HCC. In presence of serum in the cell culture media, the mRNA of the specific immunoproteasome genes and UbD were down regulated by PS‐341. In the absence of serum, the TNFa and IFNg cotreatment increased the expression of 3 immunoproteaomes proteins and the expression of UbD. Similar results were found using luciferase reporter gene downstream of the UbD promoter. In the presence of the p53 consensus sequence, the cytokine cotreatment didn't induce the activity of the promoter. In the absence of p53 sequence, the cytokine cotreatment induced the activity of promoter. The analysis of the UbD promoter sequence reveals the presence of an ISRE sequence (Interferon Sequence Responsive Element) in the activated promoter by cytokine cotreatment. TNFa and IFNg increased the expression of UbD through the ISRE sequence present on the UbD promoter. The identification of the cytokines pathway activating UbD expression could help to determine a way to down regulate it and, thus, to prevent the HCC formation. The study was supported by NIH/NIAAA grants 8116 and the Alcohol Center Grant on Liver and Pancreas P50‐011999, including the morphology core.