Human papillomaviruses: basic mechanisms of pathogenesis and oncogenicity

Abstract

Human papillomaviruses (HPVs) are small double-stranded DNA viruses that infect the cutaneous and mucosal epithelium. Infection by specific HPV types has been linked to the development of cervical carcinoma. HPV infects epithelial cells that undergo terminal differentiation and so encode multiple mechanisms to override the normal regulation of differentiation to produce progeny virions. Two viral proteins, E6 and E7, alter cell cycle control and are the main arbitrators of HPV-induced oncogenesis. Recent data suggest that E6 and E7 also play a major role in the inhibition of the host cell innate immune response to HPV. The E1 and E2 proteins, in combination with various cellular factors, mediate viral replication. In addition, E2 has been implicated in both viral and cellular transcriptional control. Despite decades of research, the function of other viral proteins still remains unclear. While prophylactic vaccines to block genital HPV infection will soon be available, the widespread nature of HPV infection requires greater understanding of both the HPV life cycle as well as the mechanisms underlying HPV-induced carcinogenesis.

The Role of p53 Gene in Cervical Carcinogenesis

“…HPVs have circular, double-stranded DNA genomes that encode eight genes, of which E6 and E7 have transforming properties. E6/E7 expression promotes chromosomal instability, foreign DNA integration, and other mutagenic events in the cell [2]. The identification of the specific genes involved, and their correlation with specific tumor properties and stages, could improve the understanding and perhaps the management of cervical carcinoma.…”

Human papillomavirus type 16 reduces the expression of microRNA-218 in cervical carcinoma cells

“…HPVs are small double-stranded DNA viruses that contain two oncogenes E6 and E7 that are involved in cellular transformation. Most low-grade cervical lesions contain HPV DNA in an episomal state, but in most cases of cervical carcinomas the HPV DNA is found integrated into the host chromosomes, increasing expression of E6 and E7 (Munger and Howley, 2002;Hebner and Laimins, 2006). The E6 protein promotes ubiquitination and proteasomal degradation of the tumor suppressor protein p53 (Huibregtse et al, 1991;Lechner et al, 1992;Band et al, 1993;Thomas et al, 1999) and PDZ domain-containing disc large protein (DLG) (Gardiol et al, 1999).…”

“…The E7 protein binds to and inactivates the function of the pRB and related tumor suppressor proteins p107 and p130 (Munger and Howley, 2002). E7 also interacts with additional cellular proteins, such as TATA-binding protein, histone H1 kinase and cyclin E (Massimi et al, 1996;Hebner and Laimins, 2006). In addition, E6/E7 expression promotes chromosomal instability, foreign DNA integration and other mutagenic events in the cell (Duensing et al, 2000;Hebner and Laimins, 2006).…”

“…E7 also interacts with additional cellular proteins, such as TATA-binding protein, histone H1 kinase and cyclin E (Massimi et al, 1996;Hebner and Laimins, 2006). In addition, E6/E7 expression promotes chromosomal instability, foreign DNA integration and other mutagenic events in the cell (Duensing et al, 2000;Hebner and Laimins, 2006). MicroRNAs (miRNAs) are small noncoding RNAs that may regulate thousands of mRNA targets (for reviews, see Lewis et al, 2005;Calin and Croce, 2006).…”

Die Infektion mit humanen Papillomaviren

“…"long control region" (LCR) reguliert. Diese besitzt u. a. Bindungsstellen für die viralen Proteine E1 und E2, welche unter normalen Umständen hierdurch die Expression der Onkogene E6 und E7 inhibieren [7].…”