Ectopic expression of hepatitis C virus core protein differentially regulates nuclear transcription factors.
The putative core protein of hepatitis C virus (HCV) regulates cellular growth and a number of cellular promoters. To further understand its effect, we investigated the role of the core protein in the endogenous regulation of two distinct transcription factors, nuclear factor-kappaB (NF-kappaB) and activating protein-1 (AP-1), and the related mitogen-activated protein kinase kinase (MAPKK) and c-Jun N-terminal kinase (JNK). Stable cell transfectants expressing the HCV core protein suppressed tumor necrosis factor (TNF)-induced NF-kappaB activation. Supershift analysis revealed that NF-kappaB consists of p50 and p65 subunits. This correlated with inhibition of the degradation of IkappaBalpha, the inhibitory subunit of NF-kappaB. The effect was not specific to TNF, as suppression in core protein-expressing cells was also observed in response to a number of other inflammatory agents known to activate NF-kappaB. In contrast to the effect on NF-kappaB, the HCV core protein constitutively activated AP-1, which correlated with the activation of JNK and MAPKK, which are known to regulate AP-1. These observations indicated that the core protein targets transcription factors known to be involved in the regulation of inflammatory responses and the immune system.
Shrivastava
A
A
Cytokine Research Laboratory, Department of Molecular Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Manna
S K
SK
Ray
R
R
Aggarwal
B B
BB
D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002455:Cell Division; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism; D015870:Gene Expression; D005814:Genes, Viral; D016174:Hepacivirus / Q000235:genetics* / Q000472:pathogenicity / Q000502:physiology*; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D020672:I-kappa B Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D019319:Okadaic Acid / Q000494:pharmacology; D009838:Oligodeoxyribonucleotides / Q000235:genetics / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014758:Viral Core Proteins / Q000235:genetics* / Q000502:physiology*
D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D009838:Oligodeoxyribonucleotides; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D014758:Viral Core Proteins; D000072000:NF-KappaB Inhibitor alpha; D019319:Okadaic Acid; D006861:Hydrogen Peroxide; D011494:Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D013755:Tetradecanoylphorbol Acetate