HPV16 E1--E4 protein is phosphorylated by Cdk2/cyclin A and relocalizes this complex to the cytoplasm.
The human papillomavirus type 16 E1--E4 protein is expressed abundantly in cells supporting viral DNA amplification, but its expression is lost during malignant progression. In cell culture, 16E1--E4 causes G2 cell cycle arrest by associating with and preventing the nuclear entry of Cdk1/cyclin B1 complexes. Here, we show that 16E1--E4 is also able to associate with cyclin A and Cdk2 during the G2 phase of the cell cycle. Only a weak association was apparent during S-phase, and progression through S-phase appeared unaffected. As with cyclin B1, the interaction of 16E1--E4 with cyclin A is dependent on residues T22/T23 and results in the accumulation of cyclin A in the cytoplasm where it colocalizes with 16E1--E4. 16E1--E4 serine 32 was found to be phosphorylated by Cdk2/cyclin A. We hypothesize that the interaction of 16E1--E4 with cyclin A may serve to increase the efficiency with which 16E1--E4 is able to prevent mitotic entry.
Division of Virology, MRC National Institute for Medical Research, London NW7 1AA, UK. cdavy@nimr.mrc.ac.uk
Clare E
CE
Davy
Mahmood
M
Ayub
Deborah J
DJ
Jackson
Papia
P
Das
Pauline
P
McIntosh
John
J
Doorbar
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D015153:Blotting, Western; D002453:Cell Cycle; D002460:Cell Line; D019925:Cyclin A / Q000378:metabolism*; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism*; D003593:Cytoplasm / Q000737:chemistry; D052162:Human papillomavirus 16 / Q000502:physiology*; D006801:Humans; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D008858:Microscopy, Phase-Contrast; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D025941:Protein Interaction Mapping; D021381:Protein Transport; D012694:Serine / Q000378:metabolism; D014764:Viral Proteins / Q000378:metabolism*
D019925:Cyclin A; D015514:Oncogene Proteins, Fusion; D014764:Viral Proteins; C072777:oncogene protein E1--E4, Human papillomavirus type 16; D012694:Serine; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2