Abrogation of a mitotic checkpoint by E2 proteins from oncogenic human papillomaviruses correlates with increased turnover of the p53 tumor suppressor protein.
Human papillomavirus (HPV) E2 and E1 proteins are required for the replication of viral genomes in vivo. We have examined the effects of increasing the level of E2 on viral and cellular replication using recombinant adenoviruses. Infection of cells which maintain HPV 31 DNA episomally with E2 recombinant adenoviruses resulted in a 5-fold increase in genome copy number as well as an S phase arrest allowing for the continued replication of cellular DNA. Similar effects on cell cycle progression were seen following infection of normal human foreskin keratinocytes, the natural host cell. The DNA content of these cells increased beyond 4N indicating that multiple rounds of replication had occurred without an intervening mitotic event. In addition, increased cyclin A and E associated kinase activity was observed, while no change was detected in cyclin B associated kinase activity or in the activation state of cdc2 kinase. Interestingly, the levels of the p53 tumor suppresser protein were dramatically reduced through a post-transcriptional mechanism following infection. These data suggest a role for E2 in regulating viral and cellular replication by abrogation of a mitotic checkpoint, which is, at least in part, controlled by p53.
Frattini
M G
MG
Department of Microbiology-Immunology, Northwestern University, Chicago, IL 60611, USA.
Hurst
S D
SD
Lim
H B
HB
Swaminathan
S
S
Laimins
L A
LA
D000256:Adenoviridae; D016203:CDC2 Protein Kinase / Q000378:metabolism; D002453:Cell Cycle; D002467:Cell Nucleus / Q000648:ultrastructure; D004279:DNA, Viral / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism* / Q000494:pharmacology; D004789:Enzyme Activation; D005434:Flow Cytometry; D015967:Gene Expression Regulation, Viral; D005822:Genetic Vectors; D006207:Half-Life; D006801:Humans; D008938:Mitosis; D027383:Papillomaviridae / Q000378:metabolism*; D011494:Protein Kinases / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism / Q000494:pharmacology; D016196:S Phase; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D014764:Viral Proteins / Q000378:metabolism* / Q000494:pharmacology
D004279:DNA, Viral; D004268:DNA-Binding Proteins; C098597:E2 protein, Human papillomavirus type 31; D011994:Recombinant Proteins; D016159:Tumor Suppressor Protein p53; D014764:Viral Proteins; D011494:Protein Kinases; C102333:histone H1 kinase; D016203:CDC2 Protein Kinase