HPV E6, E6AP and Cervical Cancer

Abstract

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 BackgroundHuman 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,

The Association of CYP1A1 Gene With Cervical Cancer and Additional SNP–SNP Interaction in Chinese Women

“…The human papilloma virus (HPV) appears to be a necessary factor in the development of almost all cases (>90%) of cervical cancer (4). The HPV E6 and E7 proteins are viral genes expressed in virtually all HPV-positive cervical carcinomas, and many experiments have shown that these are cooperative viral oncoproteins that inactivate p53 and retinoblastoma (pRb) tumor suppressors, promoting carcinogenesis (5,6). Cytochrome P450 (CYP) enzymes are pivotal to the metabolic activation of PAHs to epoxide intermediates.…”

Genetic susceptibility to cervical cancer: role of common polymorphisms in apoptosis-related genes

“…This allows for unregulated transcription of E6 and E7 genes, producing the corresponding E6 and E7 oncoproteins, respectively, through which the virus primarily exerts its oncogenic potential [28]. The E6 oncoprotein binds to E6AP ubiquitin-protein ligase, which causes constant polyubiquitination of the arguably most important tumor suppressor protein in humans, p53 [29] (Fig. 1b).…”

The implication of CRISPR/Cas9 genome editing technology in combating human oncoviruses

“…Thus, rendering E6 and E7 genes as the primary targets for therapeutic interference in HPV-associated cancer. 34 Hu et al 35 Since no sequence homology exists between E7 and any human gene, thus knocking out the E7 gene can only cause damage to the tumor cells without harming normal healthy cells. Altogether, the CRISPR/Cas9-mediated eradication of HPV is depicted in Figure 2.…”