The regulation of cell proliferation by the papillomavirus early proteins

Abstract

The human papillomavirus (HPV) E6 and E7 oncogenes have direct effects on host cell proliferation. The viral E2 protein regulates transcription of E6 and E7 and thereby has an indirect effect on cell proliferation. In HPV-induced tumours, misappropriate random integration of the viral genome into the host chromosome often leads to disruption of the E2 gene and the loss of E2 expression. This results in cessation of the virus life cycle and the deregulation of E6 and E7 and is an important step in tumourigenesis. However, prior to these integration events, E2 can interact directly with the E6 and E7 proteins and modulate their activities. E2 also interacts with a variety of host proteins, including the p53 tumour suppressor protein. Here we outline evidence that suggests a role for E2 in the regulation of cell proliferation, and we discuss the importance of this regulation in viral infection and cervical tumourigenesis.

Biology of Human Papillomavirus Infections in Head and Neck Carcinogenesis

“…HPVs critically depend on the cellular machinery for the replication of their genome [3,5]. During the course of infection in proliferating basal cells or in transformed cell systems, HPVs establish their genomes as low-copy-number, autonomously replicating episomes [3,5,19,20]. HPV DNA replicates during the S phase, in synchrony with the host cell chromosome, and the mechanism of initiation of replication is fundamentally the same as that of eukaryotic chromosomes [19].…”

“…E2 binds to LCR in HPV origin of transcription (ori) and facilitates the recruitment of E1, which is essential for viral replication [3,20]. E2 protein is expressed in three forms, a fulllength form that acts as a trans-activator, and two forms that lack the trans-activation domain.…”

“…E1 interacts with several cellular genes to synchronize the viral replication to host cell replication and is critical for G1/S transition and S phase. E1 also has an important role in retaining the episomal state of the viral molecule, i.e., keeping it separate from the host cell chromosome [3,5,19,20].…”

“…Hence, the HPVs, especially viral proteins E5, E6 and E7, have developed strategies to subvert cellular growth regulatory pathways and are able to uncouple cellular proliferation and differentiation [3,5,19,20]. E7 is the most important driver of the cell cycle deregulation (Fig.…”

“…5). The HPV E7 protein can induce cellular proliferation through several pathways by disrupting the activity of cyclin-dependent kinase (CDK) inhibitors p21 and p27, activation of CDKs and destabilization of the Rb tumor suppressor protein [for review see [20][21][22][23][24]. Rb family members (pRb, p107, p130) are instrumental in the control of cell cycle progression largely through regulation of the E2F family of transcription factors [23,25].…”