HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 VIRAL-PROTEIN-R (VPR) ARRESTS CELLS IN THE G(2) PHASE OF THE CELL-CYCLE BY INHIBITING P34(CDC2) ACTIVITY
HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 VIRAL-PROTEIN-R (VPR) ARRESTS CELLS IN THE G(2) PHASE OF THE CELL-CYCLE BY INHIBITING P34(CDC2) ACTIVITY
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DOI：
10.1128/jvi.69.11.6705-6711.1995
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发表时间：
1995-11-01
影响因子：
5.4
通讯作者：
LANDAU, NR
中科院分区：
文献类型：
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作者：
HE, JL;CHOE, S;LANDAU, NR
人类免疫缺陷病毒1型和2型以及猿猴免疫缺陷病毒的vpr辅助基因产物被认为在允许病毒核心进入未分裂细胞的核中发挥作用。最近，Rogel等人(M.E.Rogel，L.I.Wu和M.Emerman，J.Virol，69：882-888,1995)提出了VPR的第二个作用，他们表明VPR在体外阻止了慢性感染的HIV产生细胞系的建立，显然是通过使感染细胞停滞在细胞周期的G(2)/M期。在周期细胞中，从G(2)期到M期的进程是由p34(Cdc2)/细胞周期蛋白B复合体的激活驱动的，这一事件的部分原因是p34(Cdc)2的两个调节氨基酸(Thr-14和Tyr-15)的去磷酸化。我们在这里表明，VPR通过阻止p34(Cdc2)/细胞周期蛋白B复合体的激活来阻止G(2)中的细胞周期。VPR在细胞中的表达导致p34(Cdc2)保持在磷酸化的非活性状态，表达vpr的细胞中的p34(Cdc2)/细胞周期蛋白B复合体免疫沉淀在组蛋白H1激酶检测中几乎完全失活。结构活性突变p34(Cdc2)分子与Vpr共表达可缓解G(2)期停滞。这些发现有力地表明，VPR通过阻止进入M期所需的p34(Cdc2)/细胞周期蛋白B复合体的激活来阻止G(2)期的细胞。在体内，VPR可能通过阻止p34(Cdc2)的激活，延缓或阻止感染细胞的凋亡。这将增加每个受感染细胞产生的病毒数量。
The Vpr accessory gene product of human immunodeficiency virus types 1 and 2 and simian immunodeficiency virus is believed to play a role in permitting entry of the viral core into the nucleus of nondividing cells. A second role for Vpr was recently suggested by Rogel et al, (M. E. Rogel, L. I. Wu, and M. Emerman, J. Virol, 69:882-888, 1995), who showed that Vpr prevents the establishment in vitro of chronically infected HIV producer cell lines, apparently by causing infected cells to arrest in the G(2)/M phase of the cell cycle. In cycling cells, progression from G(2) to M phase is driven by activation of the p34(cdc2)/cyclin B complex, an event caused; in part, by dephosphorylation of two regulatory amino acids of p34(cdc)2 (Thr-14 and Tyr-15). We show here that Vpr arrests the cell cycle in G(2) by preventing the activation of the p34(cdc2)/cyclin B complex. Vpr expression in cells caused p34(cdc2) to remain in the phosphorylated, inactive state, p34(cdc2)/cyclin B complexes immunoprecipitated from cells expressing Vpr were almost completely inactive in a histone H1 kinase assay. Coexpression of a constitutively active mutant p34(cdc2) molecule with Vpr relieved the G(2) arrest. These findings strongly suggest that Vpr arrests cells in G(2) by preventing the activation of the p34(cdc2)/cyclin B complex that is required for entry into M phase. In vivo, Vpr might, by preventing p34(cdc2) activation, delay or prevent apoptosis of infected cells. This would increase the amount of virus each infected cell produced.