Papillomavirus E6 proteins

Howie, Heather L.; Katzenellenbogen, Rachel A.; Galloway, Denise A.

doi:10.1016/j.virol.2008.11.017

Cited by 281 publications

(242 citation statements)

References 147 publications

(216 reference statements)

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“…Several recent studies have shown that E6 and E7 bind to different cell proteins involved in the processes of adhesion, apoptosis, cell cycle, DNA repair, metabolism, signal transduction, transcription and other functions (Horikawa and Barrett, 2003;Whiteside et al, 2008;Howie et al, 2009;McLaughlin-Drubin and Mu¨nger, 2009). In addition, deregulation of the expression of several miRNAs in the host cells associated with HPV infection induced by some of its oncoproteins has been noted by several authors (Martinez et al, 2008;Reshmi and Pillai, 2008;Wang et al, 2008Wang et al, , 2009.…”

Section: Human Papilloma Virusmentioning

confidence: 99%

Viral epigenomes in human tumorigenesis

Fernández

Esteller

2010

Oncogene

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Viruses are associated with 15-20% of human cancers worldwide. In the last century, many studies were directed towards elucidating the molecular mechanisms and genetic alterations by which viruses cause cancer. The importance of epigenetics in the regulation of gene expression has prompted the investigation of virus and host interactions not only at the genetic level but also at the epigenetic level. In this study, we summarize the published epigenetic information relating to the genomes of viruses directly or indirectly associated with the establishment of tumorigenic processes. We also review aspects such as viral replication and latency associated with epigenetic changes and summarize what is known about epigenetic alterations in host genomes and the implications of these for the tumoral process. The advances made in characterizing epigenetic features in cancer-causing viruses have improved our understanding of their functional mechanisms. Knowledge of the epigenetic changes that occur in the genome of these viruses should provide us with markers for following cancer progression, as well as new tools for cancer therapy.

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Section: Human Papilloma Virusmentioning

confidence: 99%

Viral epigenomes in human tumorigenesis

Fernández

Esteller

2010

Oncogene

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“…For example, E6 binds proteins that regulate cell differentiation, adhesion, polarity, proliferation, apoptosis, gene transcription, and chromosomal stability (22,23). E6 interacts with these target proteins via several mechanisms, including two known binding motifs [the LXXLL motif (22)(23)(24)(25)(26) and the PDZ domain (22,23,27)].…”

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confidence: 99%

HPV E6 protein interacts physically and functionally with the cellular telomerase complex

Liu

Dakić

Zhang

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

109

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Telomerase activation is critical for the immortalization of primary human keratinocytes by the high-risk HPV E6 and E7 oncoproteins, and this activation is mediated in part by E6-induction of the hTERT promoter. E6 induces the hTERT promoter via interactions with the cellular ubiquitin ligase, E6AP, and with the c-Myc and NFX-1 proteins, which are resident on the promoter. In the current study we demonstrate that E6 protein interacts directly with the hTERT protein. Correlating with its ability to bind hTERT, E6 also associates with telomeric DNA and with endogenous active telomerase complexes. Most importantly, E6 increases the telomerase activity of human foreskin fibroblasts transduced with the hTERT gene, and this activity is independent of hTERT mRNA expression. Unlike its ability to degrade p53, E6 does not degrade hTERT protein in vitro or in vivo. Our studies of E6/hTERT interactions also reveal that the C-terminal tagged hTERT protein, although incapable of immortalizing fibroblasts, does immortalize keratinocytes in collaboration with the viral E7 protein. Thus, E6 protein mediates telomerase activation by a posttranscriptional mechanism and these findings provide a model for exploring the direct modulation of cell telomerase/telomere function by an oncogenic virus and suggest its potential role in both neoplasia and virus replication.cell immortalization ͉ hTERT ͉ oncoproteins ͉ papillomavirus T he HPV-16 E6 oncoprotein increases cellular telomerase activity, predominantly by inducing transcription of the hTERT gene (1-6). The hTERT protein is the catalytic, ratelimiting subunit of the telomerase enzyme complex and is selectively expressed in a small subset of normal cells (stem cells), tumor tissues, and tumor-derived cell lines (7-10). Interestingly, overexpression of hTERT or c-Myc (which transactivates the hTERT promoter) can substitute for E6 in the immortalization of primary HFKs, indicating that telomerase activation constitutes a major immortalizing function of E6 (11,12). Our previous studies and those of other laboratories indicate that E6-mediated hTERT transactivation is independent of its ability to degrade p53 or interact with PDZ proteins (11-16). However, hTERT transactivation by E6 is dependent upon its binding the cellular ubiquitin ligase, E6AP (13,14,(17)(18)(19)(20). There appear to be two critical targets for E6/E6AP on the hTERT promoter, Myc (12, 15, 16) and NFX-1 (13, 18, 21), which transactivate and transrepress the promoter respectively. The model for E6 regulation of the hTERT promoter is likely to be quite complex and it is anticipated that there might be additional targets for E6 on this promoter.In addition to activating telomerase, E6 interacts with a spectrum of cellular proteins that may contribute to HPV oncogenicity. For example, E6 binds proteins that regulate cell differentiation, adhesion, polarity, proliferation, apoptosis, gene transcription, and chromosomal stability (22,23). E6 interacts with these target proteins via several mechanisms, including two known ...

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“…These results may indicate that, in addition to transcriptional regulation, other mechanisms (such as post-transcriptional regulation) may contribute to the downregulation of expression of these genes by the HPV oncoproteins. HPV 16 E6 has been reported to induce the expression of the hTERT gene at the level of transcription [ 3 ]. In addition, a cellular factor (NFX1-123) has been shown to increase hTERT mRNA stability in the presence of HPV 16 E6.…”

Section: Discussionmentioning

confidence: 99%

“…The transforming activity of E6 and E7 is mainly mediated through the inactivation of cellular tumour suppressor proteins. High-risk HPV E6 is able to induce the functional inactivation and proteosomal degradation of p53 [ 3 ]. The E7 proteins of high-risk genital HPVs are able to bind to the retinoblastoma protein (Rb) and to the related pocket proteins (p107 and p130), release E2F transcription factors from the pocket proteins, and induce the progression of the cell cycle [ 4 -6 ].…”

Section: Introductionmentioning

confidence: 99%

Transcriptional regulation of genes involved in keratinocyte differentiation by human papillomavirus 16 oncoproteins

et al. 2014

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The life cycle of human papillomaviruses (HPVs) is strictly linked to the differentiation of their natural host cells. The HPV E6 and E7 oncoproteins can delay the normal differentiation program of keratinocytes; however, the exact mechanisms responsible for this have not yet been identified. The goal of this study was to investigate the effects of HPV16 oncoproteins on the expression of genes involved in keratinocyte differentiation. Primary human keratinocytes transduced by LXSN (control) retroviruses or virus vectors expressing HPV16 E6, E7 or E6/E7 genes were subjected to gene expression profiling. The results of microarray analysis showed that HPV 16 E6 and E7 have the capacity to downregulate the expression of several genes involved in keratinocyte differentiation. Quantitative real-time polymerase chain reaction (qRT-PCR) assays were performed to confirm the microarray data. To investigate the effects of the HPV oncoproteins on the promoters of selected keratinocyte differentiation genes, luciferase reporter assays were performed. Our results suggest that the HPV 16 E6 and/or E7 oncogenes are able to downregulate the expression of several genes involved in keratinocyte differentiation (such as desmocollin 1, keratin 4, S100 calcium-binding protein A8 and small proline-rich protein 1A), at least partially by downregulating their promoter activity. This activity of the HPV oncoproteins may have a role in the productive virus life cycle, and also in virus-induced carcinogenesis. Electronic supplementary materialThe online version of this article

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Papillomavirus E6 proteins

Cited by 281 publications

References 147 publications

Viral epigenomes in human tumorigenesis

Viral epigenomes in human tumorigenesis

HPV E6 protein interacts physically and functionally with the cellular telomerase complex

Transcriptional regulation of genes involved in keratinocyte differentiation by human papillomavirus 16 oncoproteins

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