HPV E 6 , E 6 AP and cervical cancer

Every year, approximately 470,000 new cases of cervical cancer are diagnosed and approximately 230,000 women worldwide die of the disease, with the majority (~80%) of these cases and deaths occurring in developing countries. Human papillomaviruses (HPVs) are the etiological agents in nearly all cases (99.7%) of cervical cancer, and the HPV E6 protein is one of two viral oncoproteins that is expressed in virtually all HPV-positive cancers. E6 hijacks a cellular ubiquitin ligase, E6AP, resulting in the ubiquitylation and degradation of the p53 tumor suppressor, as well as several other cellular proteins. While the recent introduction of prophylactic vaccines against specific HPV types offers great promise for prevention of cervical cancer, there remains a need for therapeutics. Biochemical characterization of E6 and E6AP has suggested approaches for interfering with the activities of these proteins that could be useful for this purpose. Publication history: Republished from Current BioData's Targeted Proteins database (TPdb; http://www.targetedproteinsdb.com). Protein pathway involvement in disease Background Human papillomaviruses (HPVs) are small DNA tumor viruses that infect cutaneous or mucosal epithelial cells, causing papillomas or warts on skin, genital tissues and the upper promyelocytic leukemia respiratory tract [1]. More than a hundred different HPV types have been characterized, and approximately a third of these infect the genital tract [2]. The genital HPV types are sexually transmitted and can be further divided into low-risk and highrisk groups according to the propensity of their induced lesions to progress to malignancy. The low-risk HPV types, such as types 6 and 11, are associated with genital warts that do not progress toward cancer, while the high-risk HPV types cause intraepithelial lesions that can progress to invasive carcinomas [3]. High-risk HPV types are associated with 99.7% of cervical cancers [4,5]. Specifically, HPV16 and HPV18 are the high-risk types most frequently associated with cervical squamous cell carcinomas (50% and 20%, respectively). The introduction of prophylactic vaccines against specific HPV types offers great promise for prevention of these cancers [6]. High-risk HPV types are also associated with approximately 25% of head and neck carcinomas (of the mouth, tonsils, esophagus and larynx, in particular) [7,8]. The HPV E6 and E7 proteins are the only two viral genes expressed in virtually all HPV-positive cervical carcinomas, and many lines of experiments have shown that these are cooperative viral oncoproteins (reviewed in [9]). The activities of E6 and E7 that are most clearly linked to carcinogenesis are their abilities to inactivate the p53 and the retinoblastoma (pRb) tumor suppressors, respectively. High-risk HPV E6 proteins bind directly to E6AP, a celluPublished: 21 October 2008 BMC Biochemistry 2008, 9(Suppl 1):S4 doi:10.1186/1471-2091-9-S1-S4 <supplement> <title> <p>Ubiquitin-Proteasome System in Disease Part 2</p> </title> <editor>John Mayer and Rob Layfield</editor> <note>Reviews</note> </supplement> This article is available from: http://www.biomedcentral. com/1471-2091/9/S1/S4 © 2008 Beaudenon and Huibregtse; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.