Human Papillomavirus Infection

Park, Jong Sup

Abstract

The pathogenesis of cervical cancer is a clinically important example of multistage epithelial tumorigenesis from the progressive neoplastic changes known as premalignant cervical intraepithelial neoplasias (CINs) to invasive cervical cancers. Infection with high-risk human papillomavirus (HPV) types, such as HPV-16 and -18, is strongly correlated with the development of cervical cancer. The malignant phenotype of high-risk types depends on the expression of two viral oncogenes, E6 and E7. A number of genetic and biochemical studies have shown that E6 and E7 proteins cooperatively exert cellular immortalization and transformation by interfering with the functions of the cellular tumor suppressor proteins, p53 and pRb, respectively. The two oncoproteins inactivate the tumor suppressor proteins in such a way that E6 binds to p53 and promotes its ubiquitin/proteosome-dependent degradation and E7 binds to the hypophosphorylated form of pRb and interferes with its binding to E2F. In addition to these features of E6 and E7, other or additional activities have been reported that the independent of p53 and pRb in the course of cellular transformation. p73 was inactivated by both high-risk and low-risk HPV E6 proteins, independent of the E6-directed degradation. The inactivation of p73 by the high-risk E6 would provide another advantage for cervical carcinogenesis. We also found that HPV E7 is functionally associated with the interferon regulatory factor (IRF)-1 tumor suppressor, a key regulator of cellular immune response. Binding assays indicate a physical interaction between IRF-1 and HPV E7 at the molecular level both in vitro and in vivo. E7 transgene expression in an inducible cell line and transgenic mice abrogates transactivation function of IRF-1 in vivo, which might be important for the elucidation of the E7-mediated immune evading mechanism that is frequently found in cervical cancer. Furthermore, the functional inactivation of p73 or IRF-1 by both high-risk and low-risk HPV E6/E7 could play an important role in the malignant transformation and benign condyloma formation of the cervix.