Abstract
Notch receptor signaling has been implicated in cellular transformation. Notchโ1 receptor expression is increased during the progression from cervical intraepithelial lesions (CIN) to invasive cervical carcinoma. Moreover, the main cellular localization of Notchโ1 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 Notchโ1 expression. Mouse and human primary cell lines were transfected with HPV16 E6 and E7 and Notchโ1 expression and activity were analyzed. We show that Notchโ1 expression and activity are upregulated by E6 and E7 independently. This was due to both transcriptional and postโtranscriptional mechanisms. A protein involved in Notch processing, Presenilinโ1 (PSโ1), was also upregulated by E6 and E7. In the presence of E6 and E7, Notchโ1 protein expression is localized in the cytoplasm. Downregulation of Notchโ1 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 E6โ and E7โmediated upregulation of Notch signaling may contribute to disruption of regular cell growth in cervical cancer. ยฉ 2003 WileyโLiss, Inc.