Human papillornavirus type 16 E1∧E4-induced G2 arrest is associated with cytoplasmic retention of active Cdk1/Cyclin B1 complexese

被引:65
作者
Davy, CE
Jackson, DJ
Raj, K
Peh, WL
Southern, SA
Das, P
Sorathia, R
Laskey, P
Middleton, K
Nakahara, T
Wang, Q
Masterson, PJ
Lambert, PF
Cuthill, S
Millar, JBA
Doorbar, J [1 ]
机构
[1] Natl Inst Med Res, Div Virol, London NW7 1AA, England
[2] Natl Inst Med Res, Div Yeast Genet, London NW7 1AA, England
[3] OSI Pharmaceut, Oxford, England
[4] Univ Wisconsin, Sch Med, McArdle Lab Canc Res, Madison, WI 53706 USA
基金
英国医学研究理事会;
关键词
D O I
10.1128/JVI.79.7.3998-4011.2005
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
Human papillomavirus type 16 (HPV16) can cause cervical cancer. Expression of the viral E1(boolean AND)E4 protein is lost during malignant progression, but in premalignant lesions, E1(boolean AND)E4 is abundant in cells supporting viral DNA amplification. Expression of 16E1(boolean AND)E4 in cell culture causes G(2) cell cycle arrest. Here we show that unlike many other G(2) arrest mechanisms, 16E1(boolean AND)E4 does not inhibit the kinase activity of the Cdk1/cyclin B1 complex. Instead, 16E1(boolean AND)E4 uses a novel mechanism in which it sequesters Cdk1/cyclin B1 onto the cytokeratin network. This prevents the accumulation of active Cdk1/cyclin B1 complexes in the nucleus and hence prevents mitosis. A mutant 16E1(boolean AND)E4 (T22A, T23A) which does not bind cyclin B1 or alter its intracellular location fails to induce G(2) arrest. The significance of these results is highlighted by the observation that in lesions induced by HPV16, there is evidence for Cdk1/cyclin B1 activity on the keratins of 16E1(boolean AND)E4-expressing cells. We hypothesize that E1(boolean AND)E4-induced G(2) arrest may play a role in creating an environment optimal for viral DNA replication and that loss of E1(boolean AND)E4 expression may contribute to malignant progression.
引用
收藏
页码:3998 / 4011
页数:14
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