HPV16 E6 and E7 oncoproteins regulate Notch‐1 expression and cooperate to induce transformation

Publisher Website
Google Scholar
Abstract
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.

This publication has 37 references indexed in Scilit: