Viral proteins of bovine papillomavirus type 4 during thedevelopment of alimentary canal tumours

doi:10.1016/S1090-0233(05)80010-3

The Veterinary Journal

Volume 154, Issue 1, July 1997, Pages 69-78

https://doi.org/10.1016/S1090-0233(05)80010-3 Get rights and content

Summary

In cattle infection of the upper alimentary canal mucosa by bovine papillomavirus type 4 (BPV-4) results in the development of papillomas which can progress to cancer in animals fed on bracken fern. This paper describes a study of the cellular and subcellular distribution of a number of different BPV4 products in experimentally-incluced BPV-4 tumours. E8 and E4 proteins were detected solely as cytoplasmic antigens in the undifferentiated and differentiated layers of the papilloma, respectively; L2 was detected solely as a nuclear antigen in the differentiated layers, whereas E7 was present in either the nucleus or the cytoplasm depending on the differentiation stage of the keratinocyte. Replicative forms of viral DNA were detected from the spinous to the squamous layers. Viral antigens were not detected during papilloma regression or in carcinomas. E8 was most prominent in early developmental stages, while E4 and L2 were most abundant in mature papillomas. E7 was present in large amounts in both early and mature stages, declining at later stages. These results suggest a temporal and spatial requirement for the expression and function of the viral proteins.

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Equine sarcoids (ES) are known globally as the most frequent skin tumour affecting horses. These tumours affect the horse’s monetary value, they can affect the horse’s welfare and can be difficult and expensive to treat. Bovine papillomavirus (BPV) is considered to be the aetiological agent of this tumour, as BPV 1, 2 and 13 have been detected in ES. This is the only known natural cross species infection by a papillomavirus. The BPV genome can be divided into two coding regions: The early region E which encodes the transforming proteins E5, E6 and E7 as well as the replication and transcription regulatory proteins E1 and E2 and the late region encoding the structural proteins of the virus L1 and L2. The E5 oncoprotein is believed to downregulate MHC 1 and as a result, escapes an immune reaction with affecting the cells cycle and eventually allows the viral affected cells to proliferate into ES. We have constructed an ELISA test by utilising the C terminal peptide of the E5 oncoprotein and explored the possibility of IgG antibodies existence in horses to the E5 oncoprotein. For this study we have examined 136 horses, some showing ES lesions (80 horses) and some without ES lesions (56 horses). By using our ELISA test, we have shown that antibodies to the E5 oncoprotein are in fact present and that from a certain level seem to be found only in ES positive horses. Therefore, proving that an immune response to this protein can be expected.
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The search for infectious agents playing a role in human carcinogenesis and their identification remain important issues. This could provide clues for a broader spectrum of cancers preventable by vaccination and accessible to specific therapeutic regimens. Yet, the various ways of interacting among different factors functioning synergistically and their different modes of affecting individual cells should bring to question the validity of the term “causation”. It also should put a word of caution into all attempts to summarize criteria for “causality” of infectious agents in cancer development. At least in the opinion of these authors, we would be much better off avoiding these terms, replacing “causal factor” by “risk factor” and grading them according to their contribution to an individual’s cancer risk.
Cancer "causation" by infections - Individual contributions and synergistic networks
2014, Seminars in Oncology
Citation Excerpt :
A bovine system indicating an interaction between a virus infection with chemical compounds has been described for the endemic occurrence of esophageal cancer in cattle.66 In areas where cattle graze on bracken fern (Pteridium aquilinum) bovine papillomavirus type 4–linked esophageal papillomatosis occurs at a high rate with subsequent conversion into malignant tumors.67 Putative carcinogens have been identified in bracken fern, in particular the glycoside ptaquiloside.
The search for infectious agents playing a role in human carcinogenesis and their identification remain important issues. This could provide clues for a broader spectrum of cancers preventable by vaccination and accessible to specific therapeutic regimens. Yet, the various ways of interacting among different factors functioning synergistically and their different modes of affecting individual cells should bring to question the validity of the term “causation”. It also should put a word of caution into all attempts to summarize criteria for “causality” of infectious agents in cancer development. At least in the opinion of these authors, we would be much better off avoiding these terms, replacing “causal factor” by “risk factor” and grading them according to their contribution to an individual’s cancer risk.
The E5 proteins
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Citation Excerpt :
Like other E5 proteins, BPV4 E5 localizes primarily to intracellular membranes, retains MHCI in the Golgi apparatus, associates with the 16K subunit of V-ATPase, and inhibits cell–cell communication (Ashrafi et al., 2000; Ashrafi et al., 2002; Faccini et al., 1996). Although BPV4 E5 is expressed in fibropapillomas in the alimentary canal (Anderson et al, 1997), its role in gastrointestinal tumorigenesis is not known. In summary, papillomavirus E5 proteins have diverse effects on cell behavior, which may contribute to transformation/carcinogenesis and the productive phase of the virus life cycle.
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 protein 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.
Expression of connexin 26 and bovine papillomavirus E5 in cutaneous fibropapillomas of cattle
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Citation Excerpt :
However, occasionally fibropapillomas may progress to squamous cell carcinomas (SCCs) (Campo, 2006; Borzacchiello and Roperto, 2008). E5, the major BPV oncoprotein, is expressed in the basal layer of the epidermis and in dermal fibroblasts (Anderson et al., 1997; McCance, 2002), and is localised on the membranes of the endoplasmic reticulum and Golgi apparatus (Pennie et al., 1993). In bovine cutaneous papillomas, the highest levels of expression of E5 are in the basal layer and in differentiating keratinocytes of the spinous and granular layers (Burnett et al., 1992; Bohl et al., 2001).
Bovine papillomaviruses (BPVs) can infect epithelial cells and fibroblasts, inducing fibropapillomas in cattle. Gap junctions are communication channels between cells composed of connexins (Cxs). This study evaluated expression of Cx26 and the major BPV oncoprotein E5 in bovine cutaneous fibropapillomas. BPV DNA was amplified from 20/20 fibropapillomas and 3/3 samples of normal skin. All fibropapillomas (20/20) were positive by immunostaining for E5, whereas the three normal skin samples were negative. Cx26 was expressed faintly in the normal skin epithelium. Positive cytoplasmic and juxtanuclear immunoreactivity for Cx26 was evident in 18/20 (90%) fibropapillomas. Western blot analysis demonstrated higher expression of Cx26 in 6/6 fibropapillomas compared to normal skin samples.
BPV-1 infection is not confined to the dermis but also involves the epidermis of equine sarcoids
2011, Veterinary Microbiology
Citation Excerpt :
With ratios of 1:1.7 (T3), 1:2.5 (T1) and 1:4 (T2), a more even distribution was noted for nodular lesions (Table 1). Using IHC, E5 oncoprotein was detected in neoplastic fibroblasts and infected epidermal cells of the basal and suprabasal layers, as observed for PV-infected human and bovine epidermis (Anderson et al., 1997; Chang et al., 2001; Borzacchiello et al., 2003). E7 was found to be expressed in neoplastic fibroblasts and in the cytoplasm of basal and lower spinous epithelial cells of tumour epidermis (Fig. 2a).
In equids, bovine papillomaviruses of type 1 (BPV-1) and less frequently type 2 induce common, locally aggressive skin tumours termed sarcoids. Whereas BPV infection in cattle usually involves the epidermis and is productive in this skin layer, infection in equids is currently thought to be abortive, with virus solely residing as multiple episomes in dermal fibroblasts. Based on recent observations that do not agree with this assumption, we hypothesised that BPV also infects equid epidermis and is active in this skin layer. To test this hypothesis, we conducted a proof-of-principle study on eight distinct sarcoids. Presence of viral DNA was addressed by qualitative and quantitative BPV-1 PCR from microdissected sarcoid epidermis, and by subsequent amplicon sequencing. Viral activity was assessed by screening sarcoid epidermis for BPV-1 protein expression using immunohistochemistry (IHC) or immunofluorescence (IF). Virus-free equine skin served as negative control throughout the assays. BPV-1 DNA was demonstrated in all sarcoid epidermis samples, with viral DNA loads ranging between 2 and 195 copies/cell. Identical BPV-1 E5 genes were identified in epidermis and dermis of each of two sarcoids, yet different E5 variants were found in individual lesions. IHC/IF revealed the presence of E5 and E7 protein in sarcoid epidermis, and L1 capsomers in the squamous layer of one lesion. These findings indicate that BPV infection also involves the epidermis, where it may occasionally be productive.

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^‡: Present address: Viral Pathogenesis Unit, Department ofClinical Sciences, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK.

^§: Present address: Department of Veterinary Pathology, University of Glasgow, Glasgow G61 1QH, UK.

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ReviewViral proteins of bovine papillomavirus type 4 during thedevelopment of alimentary canal tumours

Summary

Virology

Virology

Virology

Virology

Virology

Virology

Virology

Virology

Virology

Expression of the L2 and E7 genes of the human papillomavirus type 16 in female genital dysplasias

American Journal of Pathology

Expression of human papillomavirus type 1 E4 gene products in warts

Localization of bovine papillomavirus type 1 E5 protein to transformed basal keratinocytes and permissive dif- ferentiated cells in fibropapilloma tissue

Bovine papillomavirus type 4

Prophylactic and therapeutic vaccination against a mucosal papillomavirus

Journal of General Virology

Association of bovine papillomavirus type 2 and bracken fern with bladder cancer in cattle

Cancer Research

The presence of bovine papillomavirus type 4 DNA is not required for the progression to, or the maintenance of, the malignant state in cancers ofthe alimentary canal in cattle

Embo Journal

Experimental reproduction of the papilloma-carcinoma complex of the alimentary canal in cattle

Carcinogenesis

The human papillomavirus type 6 and 16 E5 proteins are membrane-associated proteins which associate with the 16-kilodalton pore-forming protein

Journal of Virology

An emerging function for E4

Papillomavirus Report

Identification of proteins encoded by the L1 and L2 open reading frames of human papillomavirus 1a

Journal of Virology

Identification of the human papilloma virus-1a E4 gene products

Embo Journal

Specific interaction between HPV-16 E1-E4 and cytokeratins results in collapse of the epithelial cell intermediate filament network

Nature

The bovine papillomavirus type 4 E8 protein binds to ductin and causes loss of gap junctional intercellular communication in primary fibroblasts

Journal of Virology

Review
Viral proteins of bovine papillomavirus type 4 during thedevelopment of alimentary canal tumours