PMID:15767402

Citation	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, JB and Doorbar, J (2005) Human papillomavirus type 16 E1 E4-induced G2 arrest is associated with cytoplasmic retention of active Cdk1/cyclin B1 complexes. J. Virol. 79:3998-4011
Abstract	Human papillomavirus type 16 (HPV16) can cause cervical cancer. Expression of the viral E1 E4 protein is lost during malignant progression, but in premalignant lesions, E1 E4 is abundant in cells supporting viral DNA amplification. Expression of 16E1 E4 in cell culture causes G2 cell cycle arrest. Here we show that unlike many other G2 arrest mechanisms, 16E1 E4 does not inhibit the kinase activity of the Cdk1/cyclin B1 complex. Instead, 16E1 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 E4 (T22A, T23A) which does not bind cyclin B1 or alter its intracellular location fails to induce G2 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 E4-expressing cells. We hypothesize that E1 E4-induced G2 arrest may play a role in creating an environment optimal for viral DNA replication and that loss of E1 E4 expression may contribute to malignant progression.
Links	PubMed PMC1061520 Online version:10.1128/JVI.79.7.3998-4011.2005
Keywords	Animals; CDC2 Protein Kinase/metabolism; COS Cells; Cell Line, Tumor; Cell Nucleus/chemistry; Cyclin B/metabolism; Cyclin B1; Cytoplasm/chemistry; DNA Replication; G2 Phase/physiology; Humans; Keratins/metabolism; Oncogene Proteins, Fusion/genetics; Oncogene Proteins, Fusion/physiology; Papillomaviridae/pathogenicity; Papillomaviridae/physiology; Point Mutation; Viral Proteins/genetics; Viral Proteins/physiology; Virus Replication
edit table

Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
HUMAN:CDK1		GO:0005737: cytoplasm	ECO:0000314:		C		HUMAN CDK1 // Cdk1 was found diffusely in the cytoplasm in uninfected cells and cells expressing β-galactosidase(Fig. 2B).	complete CACAO 12365
HUMAN:CDK1		GO:0005634: nucleus	ECO:0000314:		C		HUMAN CDK1 // Cdk1 was found diffusely in the nucleus of uninfected cells and in cells expressing β-galactosidase (Fig. 2B).	complete CACAO 12366
HPV16:VE4		GO:0030430: host cell cytoplasm	ECO:0000314:		C		HPV16 E4(16E1^E4) // The 16E1^E4 protein was located in the cytoplasm of the host cells that expressed the protein, (Fig. 2A and 2B).	complete CACAO 12406

References

See Help:References for how to manage references in GONUTS.