The human papillomavirus-16 E6 oncoprotein decreases the vigilance of mitotic checkpoints.
The E6 and E7 proteins of the high risk human papillomaviruses (HPVs) are consistently expressed in HPV-positive cervical carcinomas. We investigated the ability of HPV-16 E6 and E7 to disrupt mitotic checkpoints in normal diploid human cells. Acute expression of HPV-16 E6, but not HPV-16 E7, decreased the fidelity of multiple checkpoints controlling entry into and exit from mitosis. After irradiation, nearly 50% of cells containing HPV-16 E6 readily entered mitosis as opposed to less than 10% of control cells. Consistent with this, asynchronous populations of cells expressing HPV-16 E6 had increased cdc2-associated histone H1 kinase activity relative to control populations. In addition, HPV-16 E6 increased sensitivity to chemically-induced S-phase premature mitosis and decreased mitotic spindle assembly checkpoint function relative to control populations. HPV-16 E6 mutants with a reduced ability to target p53 for degradation were unable to abrogate mitotic checkpoints, suggesting a possible mechanism by which HPV-16 E6 disrupts mitotic checkpoints. Expression of a mutant p53 gene yielded an intermediate phenotype relative to HPV-16 E6, generating moderate increases in sensitivity to chemically-induced S-phase PCC and mitotic spindle disruption and a heightened propensity to enter mitosis after irradiation.
Thompson
D A
DA
Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Belinsky
G
G
Chang
T H
TH
Jones
D L
DL
Schlegel
R
R
Münger
K
K
D016203:CDC2 Protein Kinase / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D005347:Fibroblasts / Q000378:metabolism; D016195:G2 Phase / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism; D008168:Lung / Q000166:cytology; D008938:Mitosis / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D009856:Oncogene Proteins, Viral / Q000502:physiology*; D050725:Papillomavirus E7 Proteins; D011494:Protein Kinases / Q000378:metabolism; D012097:Repressor Proteins; D008941:Spindle Apparatus / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects
C068651:E6 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D012097:Repressor Proteins; C059731:oncogene protein E7, Human papillomavirus type 16; D011494:Protein Kinases; C102333:histone H1 kinase; D016203:CDC2 Protein Kinase