Hepatitis C virus core protein inhibits apoptosis via enhanced Bcl-xL expression.
Previous studies indicated that hepatitis C virus core protein influences cellular apoptosis. However, the precise mechanisms of the effects are not fully understood. Therefore, in this study, we examined the mechanisms of the effects on cell apoptosis by core protein, using transiently transfected and magnetically collected core-producing HepG2 cells. First, to elucidate the target site of core protein in the apoptotic pathway, we examined the activation of caspases after anti-Fas antibody stimulation. Core protein inhibited the apoptotic cascade downstream from caspase 8 and upstream from caspase 3. Next, to clarify more direct mechanisms of this effect, mRNA levels of several bcl-2-related genes were examined. An RNase protection assay showed that the mRNA of bcl-xl increased in the core-producing cells. We showed that this increase was mediated by the enhancement of bcl-x promoter activity by core protein through an extracellular-regulated kinase pathway. These results suggest that core protein inhibits apoptosis at the mitochondria level through augmentation of Bcl-x expression, resulting in an inhibition of caspase 3 activation.
Otsuka
Motoyuki
M
Department of Gastroenterology, University of Tokyo, Tokyo, Japan.
Kato
Naoya
N
Taniguchi
Hiroyoshi
H
Yoshida
Hideo
H
Goto
Tadashi
T
Shiratori
Yasushi
Y
Omata
Masao
M
D017209:Apoptosis; D015153:Blotting, Western; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000032:analysis / Q000378:metabolism; D002461:Cell Line, Transformed; D015536:Down-Regulation; D004792:Enzyme Precursors / Q000378:metabolism; D015870:Gene Expression; D006367:HeLa Cells; D016174:Hepacivirus / Q000502:physiology*; D006801:Humans; D008099:Liver; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D015533:Transcriptional Activation; D014162:Transfection; D014758:Viral Core Proteins / Q000502:physiology*; D051020:bcl-X Protein
C494811:BCL2L1 protein, human; D004792:Enzyme Precursors; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D014758:Viral Core Proteins; D051020:bcl-X Protein; C069130:nucleocapsid protein, Hepatitis C virus; C505407:CASP3 protein, human; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases