Thr 446 phosphorylation of PKR by HCV core protein deregulates G2/M phase in HCC cells

被引:17
作者
Alisi, A
Mele, R
Spaziani, A
Tavolaro, S
Palescandolo, E
Balsano, C
机构
[1] Policlin Umberto 1, Fdn A Cesalpino, Lab Virol Oncol Mol, I-00161 Rome, Italy
[2] Univ Aquila, Dipartimento Med Interna & Sanita Publ, Laquila, Italy
[3] Ist Super Sanita, Dipartimento Malattie Infett Parassitarie & Immun, I-00161 Rome, Italy
关键词
D O I
10.1002/jcp.20363
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Hepatitis C virus (HCV) is the major causative viral agent of cirrhosis and hepatocarcinoma (HCC). HCV core protein affects cell homeostasis, playing an important role in viral pathogenesis of HCC. We investigate the effects of HCV core protein expression on cell growth in HCC cell lines. Cell cycle distribution analysis of HepG2 polyclonal core positive cells reveals a peculiar accumulation of cells in G2/M phase. Different pathways mediate G2/M arrest: such as p53 and double strand RNA protein kinase (PKR). Flow cytometry in p53-null cells demonstrates that p53 plays only a marginal role in inducing HCV core-dependent G2/M phase accumulation that seems to be significantly affected by the functional inactivation of PKR. HCC core positive cells are characterized by a significant PKR phosphorylation in Thr 446 residue, which leads deregulation of mitosis. Moreover, we observe that the overexpression of the viral protein induces an upregulation of PKR activity, which does not correlate with an increased eIF-2 phosphorylation. This uncommon behavior of PKR suggests that its activation by HCV core protein could involve alternative PKR-dependent pathways, implicated in core-dependent G2/M accumulation. The described biological effects of HCV core protein on cell cycle could be an additional viral mechanism for both HCV resistance to interferon (IFN) and HCC HCV-related pathogenesis.
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页码:25 / 31
页数:7
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共 40 条
[31]   Hepatitis C virus and its pathogenesis [J].
Shimotohno, K .
SEMINARS IN CANCER BIOLOGY, 2000, 10 (03) :233-240
[32]   HCV core, NS3, NS5A and NS5B proteins modulate cell proliferation independently from p53 expression in hepatocarcinoma cell lines [J].
Siavoshian, S ;
Abraham, JD ;
Kieny, MP ;
Schuster, C .
ARCHIVES OF VIROLOGY, 2004, 149 (02) :323-336
[33]   Processing and functions of hepatitis C virus proteins [J].
Suzuki, R ;
Suzuki, T ;
Ishii, K ;
Matsuura, Y ;
Miyamura, T .
INTERVIROLOGY, 1999, 42 (2-3) :145-152
[34]   The emerging role of the interferon-induced PKR protein kinase as an apoptotic effector: A new face of death? [J].
Tan, SL ;
Katze, MG .
JOURNAL OF INTERFERON AND CYTOKINE RESEARCH, 1999, 19 (06) :543-554
[35]  
TAYLOR DR, 2000, SCIENCE, V287, P1555
[36]   Regulation of the G2/M transition by p53 [J].
Taylor, WR ;
Stark, GR .
ONCOGENE, 2001, 20 (15) :1803-1815
[37]   Mechanism of activation of the double-stranded-RNA-dependent protein kinase PKR - Role of dimerization and cellular localization in the stimulation of PKR phosphorylation of eukaryotic initiation factor-2 (elF2) [J].
Vattem, KM ;
Staschke, KA ;
Wek, RC .
EUROPEAN JOURNAL OF BIOCHEMISTRY, 2001, 268 (13) :3674-3684
[38]   Role for the double-stranded RNA activated protein kinase PKR in E2F-1-induced apoptosis [J].
Vorburger, SA ;
Pataer, A ;
Yoshida, K ;
Barber, GN ;
Xia, WY ;
Chiao, P ;
Ellis, LM ;
Hung, MC ;
Swisher, SG ;
Hunt, KK .
ONCOGENE, 2002, 21 (41) :6278-6288
[39]  
Wang XH, 2002, CANCER RES, V62, P1662
[40]   Cell cycle regulation of the double stranded RNA activated protein kinase, PKR [J].
Zamanian-Daryoush, M ;
Der, SD ;
Williams, BRG .
ONCOGENE, 1999, 18 (02) :315-326