Dissection of human papillomavirus E6 and E7 function in transgenic mouse models of cervical carcinogenesis.
Human cervix cancer is caused by high-risk human papillomaviruses encoding E6 and E7 oncoproteins, each of which alter function of distinct targets regulating the cell cycle, apoptosis, and differentiation. Here we determined the molecular contribution of E6 or E7 to neoplastic progression and malignant growth in a transgenic mouse model of cervical carcinogenesis. E7 increased proliferation and centrosome copy number, and produced progression to multifocal microinvasive cervical cancers. E6 elevated centrosome copy number and eliminated detectable p53 protein, but did not produce neoplasia or cancer. E6 plus E7 additionally elevated centrosome copy number and created large, extensively invasive cancers. Centrosome copy number increases and p53 loss likely contributed to malignant growth; however, dysregulated proliferation and differentiation were required for carcinogenic progression.
Riley
Rebeccah R
RR
University of California San Francisco Comprehensive Cancer Center and Department of Surgery, University of California, San Francisco 94143-0808, USA.
Duensing
Stefan
S
Brake
Tiffany
T
Münger
Karl
K
Lambert
Paul F
PF
Arbeit
Jeffrey M
JM
D000818:Animals; D017209:Apoptosis; D018385:Centrosome / Q000473:pathology; D004195:Disease Models, Animal; D004967:Estrogens / Q000633:toxicity; D005260:Female; D051379:Mice; D008822:Mice, Transgenic; D009367:Neoplasm Staging; D009856:Oncogene Proteins, Viral / Q000502:physiology*; D016366:Open Reading Frames; D027383:Papillomaviridae / Q000235:genetics; D050725:Papillomavirus E7 Proteins; D012097:Repressor Proteins; D002583:Uterine Cervical Neoplasms / Q000209:etiology* / Q000473:pathology
C068651:E6 protein, Human papillomavirus type 16; D004967:Estrogens; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D012097:Repressor Proteins; C059731:oncogene protein E7, Human papillomavirus type 16