Mechanisms of cell transformation by papillomavirus E5 proteins

DiMaio, Daniel; Mattoon, Dawn

doi:10.1038/sj.onc.1204915

Cited by 159 publications

(121 citation statements)

References 74 publications

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“…Down-regulation of MHC-I takes place at multiple levels: the transcription of the gene is reduced, the MHC-I heavy chain peptide is degraded [9] and the MHC-I complex is sequestered in the GA cisternae and prevented from reaching the cell surface [81]. The molecular mechanism by which BPV-1 E5 induces cell transformation lies in its binding to, and activation of, the cellular receptor for the platelet-derived growth factor (PDGF ) [48]. The viral oncoprotein and the receptor form stable complexes, in which the two proteins are in opposite orientation and E5 interacts with the transmembrane and juxtamembrane domains of the PDGF-R [41,50,103,128].…”

Section: E5mentioning

confidence: 99%

Bovine papillomaviruses, papillomas and cancer in cattle

Borzacchiello¹,

Roperto²

2008

Vet. Res.

167

149

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-Bovine papillomaviruses (BPV) are DNA oncogenic viruses inducing hyperplastic benign lesions of both cutaneous and mucosal epithelia in cattle. Ten (BPV 1-10) different viral genotypes have been characterised so far. BPV 1-10 are all strictly species-specific but BPV 1/2 may also infect equids inducing fibroblastic tumours. These benign lesions generally regress but may also occasionally persist, leading to a high risk of evolving into cancer, particularly in the presence of environmental carcinogenic co-factors. Among these, bracken fern is the most extensively studied. The synergism between immunosuppressants and carcinogenic principles from bracken fern and the virus has been experimentally demonstrated for both urinary bladder and alimentary canal cancer in cows whose diets were based on this plant. BPV associated tumours have veterinary and agricultural relevance in their own right, although they have also been studied as a relevant model of Human papillomavirus (HPV). Recent insights into BPV biology have paved the way to new fields of speculation on the role of these viruses in neoplastic transformation of cells other than epithelial ones. This review will briefly summarise BPV genome organization, will describe in greater detail the functions of viral oncoproteins, the interaction between the virus and co-carcinogens in tumour development; relevant aspects of immunity and vaccines will also be discussed.

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Section: E5mentioning

confidence: 99%

Bovine papillomaviruses, papillomas and cancer in cattle

Borzacchiello¹,

Roperto²

2008

Vet. Res.

167

149

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“…E5 activates platelet-derived growth factor (PDGF) breceptor tyrosine kinase in a ligand-independent fashion. BPV-1 E5 proteins have been shown to bridge two molecules of transmembrane PDGF receptors, resulting in receptor dimerization, activation and recruitment of cell signalling and proliferative proteins (DiMaio & Mattoon, 2001). In addition, BPV-1 E5 binds to the 16 kDa transmembrane subunit of vacuolar H + -ATPase (Goldstein et al, 1991), impairing the acidification of the Golgi apparatus and other intracellular organelles.…”

Section: E4 and E5mentioning

confidence: 99%

Lack of the canonical pRB-binding domain in the E7 ORF of artiodactyl papillomaviruses is associated with the development of fibropapillomas

Narechania

Terai

Chen

et al. 2004

Journal of General Virology

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The L-X-C-X-E pRB-binding motif of papillomavirus (PV) E7 proteins has been implicated in the immortalization and transformation of the host cell. However, sequencing of the complete genomes of bovine papillomavirus type 3 (BPV-3), bovine papillomavirus type 5 (BPV-5), equine papillomavirus (EQPV) and reindeer (Rangifer tarandus) papillomavirus (RPV) supports the notion that the pRB-binding motif is not ubiquitous among E7 proteins in the PV proteome. Key among the animal groups that lack the pRB-binding domain are the artiodactyl PVs, including European elk PV (EEPV), deer PV (DPV), reindeer PV (RPV), ovine PVs types 1 and 2 (OvPV-1 and -2) and bovine PVs 1, 2 and 5 (BPV-1, -2 and -5). Whereas the presence of the pRB-binding domain is normally associated with papillomas, the artiodactyl PVs are marked by the development of fibropapillomas on infection. Previous studies emphasized the role of E5 in the pathogenic mechanism of fibropapilloma development, but correlation between the lack of an E7 pRB-binding domain and the unique pathology of the artiodactyl PVs suggests a more complicated mechanism and an early evolutionary divergence from a pRB-binding ancestor. INTRODUCTIONPapillomaviruses (PVs) are highly species-specific pathogens. They form a heterogeneous group of closed-circular, double-stranded DNA viruses measuring about 8 kb in size (Sundberg et al., 1996). Most PVs target the basal cells of dermal or mucosal epithelia (Cheville & Olson, 1964), and infection has been implicated in both benign and malignant lesions of epithelia in a broad range of animals (Sundberg & O'Banion, 1989). Though almost all known human PVs (HPVs) infect dermal or mucosal surfaces, in some animal PVs, most notably in the artiodactyl ruminant PVs, fibroblasts appear to be the primary target cells (Sundberg et al., 1985). However, regardless of species, infection generally manifests as a papilloma or fibropapilloma, and follows a cytopathic mechanism of cell proliferation (Sundberg et al., 1996). Historically, PVs had been classified according to their tissue tropism, and this grouping was supported by later phylogenetic analysis of PV sequence data (Chan et al., 1995;de Villiers, 2001;Myers, 1994). PV phylogenies typically subdivide into mucosal/genital HPVs, cutaneous EV HPVs and three main animal PV clades: the artiodactyl ruminant PVs, the distant avian PV group and a group containing canine, feline, rabbit and rodent PV types. However, sequence analysis has highlighted some significant exceptions. BPV-3, BPV-4 and BPV-6 do not group with the artiodactyl PVs, but instead form an isolated taxon (Jarrett et al., 1984), and HPV-1, HPV-41 and HPV-63 are most closely related to the canine and feline PVs, sharing little similarity to HPVs in either the mucosal or the cutaneous groups (Egawa et al., 1993).Although most work in the area has focused on HPVs, an ever-increasing number of animal PV isolates have been sequenced. These animal PVs share key clinical features of GenBank data deposited: bovine papillomavirus 3, AF486184; bo...

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“…Additionally, many studies have shown that the BPV-1 E5 protein transforms cells by binding to and activating the cellular b receptor for the platelet-derived growth factor (PDGF b) (Petti et al, 1991(Petti et al, , 1997Petti and DiMaio, 1992;DiMaio et al, 2000;DiMaio and Mattoon, 2001). Evidence suggests that receptor activation by the E5 protein is induced upon its dimerization (Lai et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Bovine papillomavirus E5 oncoprotein binds to the activated form of the platelet-derived growth factor β receptor in naturally occurring bovine urinary bladder tumours

et al. 2005

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Studies regarding the functions of the bovine papillomavirus (BPV) E5 oncoprotein in vivo are lacking and no E5-mediated mechanism underlying epithelial carcinogenesis is known. We have shown that BPV-2 DNA is present in the majority of naturally occurring urinary bladder tumours of cattle and that E5 is expressed in the cancer cells. Here we show that the interaction between the platelet-derived growth factor (PDGF) b receptor and BPV E5, described in vitro in cultured cells, takes place in vivo in bovine urinary bladder cancers. In these cancers, E5 and PDGF b receptor colocalize, as shown by confocal microscopy, and physically interact, as shown by coimmunoprecipitation. Furthermore, the PDGF b receptor associated with E5 is highly phosphorylated, suggesting the functional activation of the receptor upon E5 interaction. Our results demonstrate, for the first time, that E5-PDGF b receptor interaction occurs during the natural history of bovine urinary bladder tumours, suggesting an important role for E5 in carcinogenesis. Finally, the system provides a suitable animal model of papillomavirus-associated cancer to test therapeutic vaccination against E5. Successful bladder tumour regression would provide a valuable model for therapeutic vaccination against papillomavirus-associated tumours.

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Mechanisms of cell transformation by papillomavirus E5 proteins

Cited by 159 publications

References 74 publications

Bovine papillomaviruses, papillomas and cancer in cattle

Bovine papillomaviruses, papillomas and cancer in cattle

Lack of the canonical pRB-binding domain in the E7 ORF of artiodactyl papillomaviruses is associated with the development of fibropapillomas

Bovine papillomavirus E5 oncoprotein binds to the activated form of the platelet-derived growth factor β receptor in naturally occurring bovine urinary bladder tumours

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