Quantitative Measurement of Human Papillomavirus Type 16 E5 Oncoprotein Levels in Epithelial Cell Lines by Mass Spectrometry

Sahab, Ziad J.; Sudarshan, Sawali R.; Li, Xuefeng; Zhang, Yiyu; Kirilyuk, Alexander; Kamonjoh, Christopher M.; Simić, Vera; Dai, Yuhai; Byers, Stephen W.; Doorbar, John; Suprynowicz, Frank A.; Schlegel, Richard

doi:10.1128/jvi.01032-12

Cited by 18 publications

(10 citation statements)

References 59 publications

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“…22 Finally, the E5 protein was identified by mass spectrometry in CaSki cells giving the definitive proof that HPV-16 E5 does exist and it may contribute to the malignant phenotype of some cervical cancers, even in cells exclusively containing an integrated HPV genome. 23 Thus, E5 may play a role in carcinogenesis and must be present in early stages. Expression of HPV-16 E5 was detected by immunohistochemistry, in LSILs, HSILs and cervical carcinomas.…”

Section: Discussionmentioning

confidence: 99%

HPV 16 E5 oncoprotein is expressed in early stage carcinogenesis and can be a target of immunotherapy

Paolini¹,

Curzio²,

Cordeiro

et al. 2016

Human Vaccines & Immunotherapeutics

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HPV16 persistent infection is a well-known condition that precedes human cancer development. High risk HPV E5 proteins cooperate with E6/E7 oncogenes to promote hyper-proliferation of infected cells leading to possible cancer progression. Thus, presence of E5 viral transcripts could be a key marker of active infection and, in turn, a target of immunotherapy. Purpose of the study is to detect E5 transcripts in clinical samples and to explore the activity of novel anti-HPV16 E5 DNA vaccines. HPV transcripts were detected by PCR with specific primers encompassing the splice-donor sites of E5 transcript. For E5-based immunotherapies, 2 E5-based versions of DNA vaccines carrying whole E5 gene or a synthetic multiepitope gene were improved by fusion to sequence of PVX coat protein. These vaccines were challenged with a new luminescent animal model based on C3-Luc cell line. E5 transcripts were detected in clinical samples of women with HPV positive low-grade SIL, demonstrating the validity of our test. In C3 pre-clinical mouse model, vaccine candidates were able to induce a strong cellular immunity as indicated by ELISPOT assays. In addition, E5-CP vaccines elicited strong anti-tumor effects as showed by decreased tumor growth monitored by animal imaging. The tumor growth inhibition was comparable to those obtained with anti-E7 DNA vaccines. In conclusion, detection of E5 transcripts in clinical samples indicates that E5 is a possible target of immunotherapy. Data from pre-clinical model demonstrate that E5 genetic immunization is feasible, efficacious and could be utilized in clinical trials.

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Section: Discussionmentioning

confidence: 99%

HPV 16 E5 oncoprotein is expressed in early stage carcinogenesis and can be a target of immunotherapy

Paolini¹,

Curzio²,

Cordeiro

et al. 2016

Human Vaccines & Immunotherapeutics

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“…In human cervical cancers, the HPV18 E5 gene is often deleted upon integration of the viral DNA into the host cell genome (Schwarz et al, 1985), and detection of the E5 protein in cervical cancers has proven difficult. However, the viral genome persists as a plasmid in some HPV16-positive cervical carcinomas (Choo et al, 1987; Cullen et al, 1991; Matsukura, Koi, and Sugase, 1989), and the 16E5 protein has been detected in precancerous and malignant HPV16-positive cervical lesions (Chang et al, 2001; Kell et al, 1994; Sahab et al, 2012), suggesting that HPV E5 may contribute to malignant progression. Such a role is supported by the finding that 16E5 contributes to both the promotion and progression stages of skin carcinogenesis in transgenic mice (Maufort et al, 2007).…”

Section: Human Papillomavirus E5 Proteinsmentioning

confidence: 99%

The E5 proteins

2013

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The E5 proteins are short transmembrane proteins encoded by many animal and human papillomaviruses. These proteins display transforming activity in cultured cells and animals, and they presumably also play a role in the productive virus life cycle. The E5 proteins are thought to act by modulating the activity of cellular proteins. Here, we describe the biological activities of the best-studied E5 proteins and discuss the evidence implicating specific protein targets and pathways in mediating these activities. The primary target of the 44-amino acid BPV1 E5 is the PDGF β receptor, whereas the EGF receptor appears to be an important target of the 83-amino acid HPV16 E5 protein. Both E5 proteins also bind to the vacuolar ATPase and affect MHC class I expression and cell-cell communication. Continued studies of the E5 proteins will elucidate important aspects of transmembrane protein-protein interactions, cellular signal transduction, cell biology, virus replication, and tumorigenesis.

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“…Unlike E6 and E7, HPV-16 E5 is highly hydrophobic and is predicted to comprise three TMDs within its 83 aa sequence Wetherill et al, 2012). E5 induces anchorage-independent growth in culture (Leechanachai et al, 1992) and tumour formation in transgenic mouse models (Maufort et al, 2007), with expression detectable in human malignancies (Cavuslu et al, 1996;Hsieh et al, 2000;Sahab et al, 2012). E5 impairs endosomal maturation, thereby stabilizing epidermal growth factor receptor signalling, and leading to increased extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase activity Genther Williams et al, 2005;Leechanachai et al, 1992;Pedroza-Saavedra et al, 2010;Pim et al, 1992;Rodríguez et al, 2000;Straight et al, 1993;Suprynowicz et al, 2010;Tomakidi et al, 2000).…”

Section: Dna Virus Viroporinsmentioning

confidence: 99%

Viroporins: structure, function and potential as antiviral targets

Scott

Griffin

2015

Journal of General Virology

120

146

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The channel-forming activity of a family of small, hydrophobic integral membrane proteins termed 'viroporins' is essential to the life cycles of an increasingly diverse range of RNA and DNA viruses, generating significant interest in targeting these proteins for antiviral development. Viroporins vary greatly in terms of their atomic structure and can perform multiple functions during the virus life cycle, including those distinct from their role as oligomeric membrane channels. Recent progress has seen an explosion in both the identification and understanding of many such proteins encoded by highly significant pathogens, yet the prototypic M2 proton channel of influenza A virus remains the only example of a viroporin with provenance as an antiviral drug target. This review attempts to summarize our current understanding of the channel-forming functions for key members of this growing family, including recent progress in structural studies and drug discovery research, as well as novel insights into the life cycles of many viruses revealed by a requirement for viroporin activity. Ultimately, given the successes of drugs targeting ion channels in other areas of medicine, unlocking the therapeutic potential of viroporins represents a valuable goal for many of the most significant viral challenges to human and animal health.

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Quantitative Measurement of Human Papillomavirus Type 16 E5 Oncoprotein Levels in Epithelial Cell Lines by Mass Spectrometry

Cited by 18 publications

References 59 publications

HPV 16 E5 oncoprotein is expressed in early stage carcinogenesis and can be a target of immunotherapy

HPV 16 E5 oncoprotein is expressed in early stage carcinogenesis and can be a target of immunotherapy

The E5 proteins

Viroporins: structure, function and potential as antiviral targets

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