Activation of RB/E2F signaling pathway is required for the modulation of hepatitis C virus core protein-induced cell growth in liver and non-liver cells.
Hepatitis C virus (HCV) core protein is a multifunctional protein that affects transcription and cell growth in vitro and in vivo. Here, we confirm the proliferative activities of core protein in liver and non-liver cells and delineate part of the mechanism whereby core protein promotes cell growth. We show that core protein suppresses the expression of tumor suppressor protein p53 and cyclin-dependent kinase (CDK) inhibitor p21 and enhances the activation of cyclin-dependent kinase 2 (CDK2), the phosphorylation of retinoblastoma (Rb), the activation of the transcription factor E2F-1, and the expression of E2F-1 and S phase kinase-interacting protein 2 (SKP2) genes. Pretreatment of core protein-expressing cells with the inhibitor of CDK2, Butyrolactone I, abolished the phosphorylation of Rb, the activation of E2F-1, and inhibited the expression of E2F-1 gene and cell growth induced. Consistent with these findings, we define a new signaling pathway whereby the HCV core protein mediates cell growth in infected cells.
Hassan
Mohamed
M
Faculty of Medicine, Institute of Pathology, University of Düsseldorf, Mooren Str. 5, 40225 Düsseldorf, Germany. Hassan@med.uni-duesseldorf.de
Ghozlan
Hanan
H
Abdel-Kader
Ola
O
D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000494:pharmacology; D015152:Blotting, Northern; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002460:Cell Line; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D018076:DNA, Complementary / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006367:HeLa Cells; D016174:Hepacivirus / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008156:Luciferases / Q000378:metabolism; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012313:RNA / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism; D015398:Signal Transduction; D013778:Tetrazolium Salts / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D013936:Thymidine / Q000737:chemistry / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D018797:Cell Cycle Proteins; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D004791:Enzyme Inhibitors; D047428:Protein Kinase Inhibitors; D016160:Retinoblastoma Protein; D013778:Tetrazolium Salts; D013844:Thiazoles; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D012313:RNA; C082868:butyrolactone I; D008156:Luciferases; C022616:thiazolyl blue; D015107:4-Butyrolactone; D013936:Thymidine