Human papillomavirus E6 and E7 oncoproteins as risk factors for tumorigenesis

Abstract

Human papillomavirus (HPV) is small, double-stranded DNA virus that infects mucosal and cutaneous epithelial tissue. HPV is sexually transmitted and the viral DNA replicates extrachromosomally. The virus is non-enveloped and has an icosahedral capsid. There are approximately 118 types of HPV, which are characterized as high-risk or low- risk types. High-risk HPVs cause malignant transformation while the low-risk ones cause benign warts and lesions. The expression of E6 and E7 is normally controlled during the normal viral life cycle when viral DNA replicates extrachromosomally. HPV E6 and E7 oncoproteins are overexpressed when the viral genome integrates into the host DNA.Deregulated overexpression of E6 and E7 oncoproteins can cause several changes in cellular pathways and functions leading to malignant transformation of cells and tumorigenesis. In this review, we focus on several cellular mechanisms and pathways that are altered in the presence of E6 and E7, the target proteins of E6 and E7 inside the host cell and how they contribute to the development of the transformed phenotype.

Molecular pathogenesis of cervical cancer

“…E7 binding to pRb results in proteosomal degradation of pRb and the unrestricted transcriptional activity of E2F. [31][32][33] Direct binding of E7 to E2F also ensures transcriptional activity that maintains the epithelial cell so they are always ready to enter S phase. E2F regulates the S phase of the cell cycle by control of cyclins, specifically cyclins A and E. Through the pRb inhibition and direct E2F induction mentioned above, E7 drives cell proliferation with increased levels of cyclins and also inhibits the activities of cyclin-dependent kinase inhibitors (CKI), p21 and p27.…”

Human Papillomavirus Screening in North Indian Women

“…There are approximately 130,000 new cases of cervical cancer in India per year and the age-standardized incidence rate is 30.7 per 100,000 (Dabash et al, 2005). The link between genital HPV infections and cervical cancer was first demonstrated in the early 1980s by Harold zur Hausen, a German virologist; although HPV is considered as a major causative agent of cervical cancer, yet the viral infection alone is not sufficient for cancer progression and/or malignancy (Ganguly and Parihar, 2009).…”

Revealing highly conserved regions in the E6 protein among distinct human papillomavirus types using comparative analysis of multiple sequence alignments

“…It is yet well elucidated that high risk genotypes lead to the development of cervical cancer and are also associated with other mucosal anogenital, head and neck tumors. The HPV genome is approximately 8 kb in length and is divided into three regions, the non-coding long control region (LCR, ~1 kb), and the protein coding early (E, ~4 kb) and late (L, ~3 kb) regions (Ganguly and Parihar, 2009). The viral genome encodes six early (E1, E2, E4, E5, E6 and E7) and two late (L1 and L2) proteins.…”

“…HPV E6 and E7 genes encode oncoproteins that cause transformation of the host cell, whose action is involved in maintenance of the HPV genome extrachromosomally. Since HPV immortalisation of keratinocytes in vitro has been identified as an important step in tumor progression in vivo, some studies have provided strong experimental supports for the hypothesis that the maintenance and expression of E6 and E7 proteins observed in human cervical carcinomas has pathologic significance (Hawley-Nelson et al, 1989;Ganguly and Parihar, 2009). The E6 protein in high risk HPV genotypes has been reported to prevent apoptosis by a p53-independent mechanism which involves inhibition of bax gene expression and degradation of Bax protein in human keratinocytes, resulting in inhibition of apoptosis and therefore cells accumulate mutations in their DNA (Magal et al, 2005).…”

“…Using multiple sequence alignments, the purpose of the present study was to perform comparative analysis of E6 protein segments between high and low risk HPV genotypes. For these analyses, E6 protein segments present in HPV 16 and 18 (high risk and virulent HPV types) and in HPV11 and 06A (low risk and non-virulent HPV types) were selected (Ganguly and Parihar, 2009). Initially, amino acid sequences of E6 protein from these four genotypes were searched using the computational algorithm UniProtKB/Swiss-Prot that provides a high quality annotated and non-redundant protein sequence database (Lesk, 2002;Jungo et al, 2012).…”