Regulation of Telomerase by Human Papillomaviruses

Abstract

Nearly 20% of cancers worldwide have a component of their etiology that is due to infectious agents. In some cases, infection has an indirect effect, such as the immunosuppression caused by HIV or the inflammation caused by Helicobacter pylori, but in other cases, such as human papillomaviruses (HPVs), viral gene products persist in the cancer and directly promote neoplasia. Understanding the mechanisms by which the viral genes disrupt the checkpoints that normally protect cells from cancer will likely provide insights into cancers in which the underlying critical abnormalities are more difficult to discern.Both epidemiologic observations and molecular data firmly support a causal role for a group of HPVs in the etiology of virtually 100% of cervical carcinomas, as well as the majority of other anogenital cancers and a subset of head and neck cancers (Cogliano et al. 2005). Of these HPV types, HPV-16 DNA is found in more than 50% of tumors (Walboomers et al. 1999). Two viral genes, E6 and E7, are invariably retained and expressed in cervical cancers, and together E6 and E7 efficiently immortalize human epithelial cells. The E7 protein associates with the retinoblastoma (Rb) family of proteins through a LXCXE motif and promotes the ubiquitin-mediated degradation of Rb, p107, and p130 (Munger et al. 2001). Degradation of Rb is necessary but not sufficient for E7's role in cellular immortalization, which also requires sequences in the carboxy-terminal zinc-like finger (Helt and Galloway 2001). HPV-16 E6 associates with a cellular protein, E6AP, and together the complex functions as a ubiquitin ligase (Huibregtse et al. 1993). The p53 tumor suppressor is the best-studied target of E6/E6AP, and its degradation eliminates several checkpoints that normally maintain genetic stability (Kessis et al. 1993;Demers et al. 1994).Disruption of the Rb and p53 pathways is critical for transformation of many human cell types, but it is also essential to prevent telomere shortening (Hahn et al. 1999). In some strains of human fibroblasts, the introduction of hTERT, the catalytic subunit of telomerase, is sufficient for immortalization (Bodnar et al. 1998;Kiyono et al. 1998;Vaziri and Benchimol 1998;Wang et al. 1998). Telomerase may play additional roles in tumorigenic transformation, because hTERT was necessary for transformation of cells that maintained long telomeres by the ALT pathway (Stewart et al. 2002). Nearly all tumors and cells transformed in culture express hTERT at levels that provide sufficient telomerase activity to keep telomeres above a critically short level (Kim et al. 1994). Multiple mechanisms are likely responsible for regulation of telomerase activity, including changes in transcription factors (Xu et al. 2001), loss of transcriptional repressors (Horikawa et al. 1998;Ducrest et al. 2001;Lin and Elledge 2003), changes in chromatin structure (Takakura et al. 2001;Hou et al. 2002), and altered levels of telomere-binding proteins (van Steensel et al. 1998). Additionally, cancers may arise in stem cells in which ...

Human papillomavirus molecular biology and disease association

“…Mechanistically, it is thought that phosphorylation regulates E6 binding to PDZ‐domain proteins and creates an alternative binding‐site, which allows E6 to associate with members of the cellular 14‐3‐3 protein family . The high‐risk E6 proteins are also characterized by an ability to upregulate telomerase activity and to maintain telomere integrity during repeated cell divisions, as well as by their ability to mediate p53 degradation within the cell. Both high‐risk and low‐risk E6 proteins inactivate p53 function, which suggests an important role in the virus life cycle, but only high‐risk types stimulate its ubiquitination and proteosome‐dependent degradation (see section on cancer progression below) .…”

Human papillomavirus molecular biology

“…This action blocks the anti proliferative and pro apoptotic activities of p53 in response to DNA damage and cellular stress caused by aberrant S-phase entry [69]. HR HPV E6 expression also upregulates telomerase activity, allowing the maintenance of telomere integrity despite repeated cell divisions [70–72]. Additionally, HR HPV E6 proteins target cellular PDZ domain containing proteins that regulate cell contact and signaling pathways [73, 74].…”

HPV E7 contributes to the telomerase activity of immortalized and tumorigenic cells and augments E6-induced hTERT promoter function

“…We and others have shown that E6 appears to activate hTERT transcription through Myc binding sites in the hTERT promoter (Gewin and Galloway, 2001;Oh, Kyo, and Laimins, 2001;Veldman et al, 2001). However, E6 does not induce Myc expression (Galloway et al, 2005;Gewin and Galloway, 2001;Oh, Kyo, and Laimins, 2001;Veldman et al, 2001) nor increase Myc binding to the hTERT promoter (Galloway et al, 2005;Sekaric, Cherry, and Androphy, 2008;Veldman et al, 2003); Myc protein binds to the promoter in the presence or absence of E6 protein in keratinocytes (Galloway et al, 2005;Sekaric, Cherry, and Androphy, 2008;Veldman et al, 2003). Interestingly, E6 associates with Myc in vivo and in vitro and both bind to the core hTERT promoter (Veldman et al, 2003).…”