HPV16 E6 and E7 oncoproteins regulate Notch-1 expression and cooperate to induce transformation.
Notch receptor signaling has been implicated in cellular transformation. Notch-1 receptor expression is increased during the progression from cervical intraepithelial lesions (CIN) to invasive cervical carcinoma. Moreover, the main cellular localization of Notch-1 protein changes from cytoplasmic to nuclear with the transition from CIN III to microinvasive carcinoma. Since the E6 and E7 proteins encoded by human papilloma virus (HPV) are a causative agent of cervical carcinoma, this study determined whether E6 and E7 protein expression causes the observed upregulation in Notch-1 expression. Mouse and human primary cell lines were transfected with HPV16 E6 and E7 and Notch-1 expression and activity were analyzed. We show that Notch-1 expression and activity are upregulated by E6 and E7 independently. This was due to both transcriptional and post-transcriptional mechanisms. A protein involved in Notch processing, Presenilin-1 (PS-1), was also upregulated by E6 and E7. In the presence of E6 and E7, Notch-1 protein expression is localized in the cytoplasm. Downregulation of Notch-1 expression in a human cervical carcinoma cell line expressing E6/E7 caused striking inhibition of proliferation in vitro and tumorigenicity in vivo. These data suggest that E6- and E7-mediated upregulation of Notch signaling may contribute to disruption of regular cell growth in cervical cancer.
Weijzen
Sanne
S
Cardinal Bernardin Cancer Center, Loyola University Chicago, Cancer Immunology Program, Maywood, Illinois, USA.
Zlobin
Andrei
A
Braid
Mike
M
Miele
Lucio
L
Kast
W Martin
WM
D000818:Animals; D030161:Avian Proteins; D002455:Cell Division / Q000502:physiology; D002460:Cell Line; D002470:Cell Survival / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D002584:Cervix Uteri / Q000166:cytology; D004847:Epithelial Cells / Q000166:cytology / Q000502:physiology; D005260:Female; D051858:Forkhead Transcription Factors; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D015513:Oncogene Proteins; D009856:Oncogene Proteins, Viral / Q000235:genetics* / Q000378:metabolism*; D050725:Papillomavirus E7 Proteins; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D012097:Repressor Proteins; D014157:Transcription Factors; D002583:Uterine Cervical Neoplasms / Q000235:genetics / Q000503:physiopathology / Q000821:virology; D014764:Viral Proteins
D030161:Avian Proteins; C068651:E6 protein, Human papillomavirus type 16; D051858:Forkhead Transcription Factors; D008565:Membrane Proteins; C497762:Notch1 protein, mouse; D015513:Oncogene Proteins; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D011518:Proto-Oncogene Proteins; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D012097:Repressor Proteins; D014157:Transcription Factors; D014764:Viral Proteins; C059731:oncogene protein E7, Human papillomavirus type 16; C490425:v-qin protein, Avian sarcoma virus 31