High-risk but not low-risk HPV E2 proteins bind to the APC activators Cdh1 and Cdc20 and cause genomic instability.
Human papillomaviruses (HPVs) from the high-risk group are associated with cervical cancer, in contrast to HPVs from the low-risk group which are associated with benign lesions of the genital tract. Here, we show that high-risk, but not low-risk HPV E2 proteins, promote a mitotic block, often followed by metaphase-specific apoptosis, and which is independent of the viral oncogenes E6 and E7. High-risk HPV E2-expressing cells also show polyploidy, chromosomal mis-segregation and centrosome amplification leading to genomic instability. We link these defects to a specific and unusually strong interaction between high-risk E2 and both Cdc20 and Cdh1, two activators of the Anaphase Promoting Complex (APC), abnormal localization of Cdh1, and accumulation of APC substrates like cyclin B, in vivo. The finding that high-risk, but not low-risk HPV E2 proteins, induce genomic instability, raises the intriguing possibility that E2 proteins play a role in the oncogenic potential of high-risk papillomaviruses.
Bellanger
Sophie
S
Unité Expression Génétique et Maladies, CNRS FRE 2850, Institut Pasteur, Paris, France.
Blachon
Stéphanie
S
Mechali
Francisca
F
Bonne-Andrea
Catherine
C
Thierry
Françoise
F
D064173:Anaphase-Promoting Complex-Cyclosome; D015703:Antigens, CD; D015820:Cadherins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D064199:Cdc20 Proteins; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000378:metabolism* / Q000502:physiology; D042822:Genomic Instability / Q000235:genetics; D052162:Human papillomavirus 16 / Q000378:metabolism* / Q000472:pathogenicity; D052161:Human papillomavirus 18 / Q000378:metabolism* / Q000472:pathogenicity; D052163:Human papillomavirus 6 / Q000378:metabolism; D006801:Humans; D009856:Oncogene Proteins, Viral / Q000378:metabolism* / Q000502:physiology; D011485:Protein Binding / Q000235:genetics; D012307:Risk Factors; D043743:Ubiquitin-Protein Ligase Complexes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; D064199:Cdc20 Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C054855:E2 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral; C069102:oncogene protein E2, Human papillomavirus type 18; C577488:CDC20 protein, human; D043743:Ubiquitin-Protein Ligase Complexes; D064173:Anaphase-Promoting Complex-Cyclosome