The role of cytokines in UbD promoter regulation and Mallory-Denk body-like aggresomes.
Mallory-Denk bodies (MDBs) are found in chronic liver diseases. Previous studies showed that diethyl-1,4-dihydro-2,4,6-trimethyl-3,5-pyridinedicarboxylate (DDC) induced formation of MDBs and the up regulation of UbD expression in mouse liver. UbD is a protein over expressed in hepatocellular carcinomas. It is a potential preneoplastic marker in the mouse. It is hypothesized that inflammatory cytokines play a critical role in UbD up regulation and MDB formation. TNFa and IFNg treatment of HCC cell line Hepa 1-6, induced the expression of UbD and the expression of genes coding for the immunoproteasome (LMP2, LMP7, and MECL-1 subunits). TNFa and IFNg induced the activity of the UbD promoter, using a luciferase assay. The cotreatment with TNFa and IFNg induced the activity of the UbD promoter through an Interferon Sequence Responsive Element (ISRE). In addition, long term treatment with TNFa and IFNg induced the formation of MDB-like aggresomes in Hepa 1-6 cells, which emphasizes the role of inflammation in the formation of MDBs leading to the formation of liver tumors, in the mouse. Identifying the mechanism that regulates gene expression of UbD supports the hypothesis that down regulation of UbD and the proinflammatory gene expression would prevent MDB and HCC formations. Previous studies indicate that S-adenosylmethionine or betaine prevented IFNg induced UbD and MDB formations.
Oliva
Joan
J
Department of Pathology, LABioMed, Torrance, CA 90502, USA.
Bardag-Gorce
Fawzia
F
Lin
Andrew
A
French
Barbara A
BA
French
Samuel W
SW
D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D007124:Immunoenzyme Techniques; D002479:Inclusion Bodies / Q000473:pathology*; D007371:Interferon-gamma / Q000494:pharmacology; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009097:Multienzyme Complexes / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000187:drug effects*; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014452:Ubiquitins / Q000235:genetics* / Q000378:metabolism
D016207:Cytokines; D009097:Multienzyme Complexes; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C109184:UBD protein, human; D014452:Ubiquitins; C071313:LMP-2 protein; D007371:Interferon-gamma; D003546:Cysteine Endopeptidases; C077436:LMP7 protein; C098948:PSMB10 protein, human; D046988:Proteasome Endopeptidase Complex