Cutaneous and Mucosal Human Papillomavirus E4 Proteins Form Intermediate Filament-like Structures in Epithelial Cells

Roberts, Sally; Ashmole, Ian; Johnson, G. D.; Kreider, John W.; Gallimore, Phillip H.

doi:10.1006/viro.1993.1578

Cited by 69 publications

(83 citation statements)

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“…A number of studies have indicated that the differentiation program in epithelial tissue harbouring HPV infection is disrupted (Nakahara et al, 2005;Roberts et al, 1993;Bryan and Brown, 2000;Doorbar et al, 1991;Wang et al, 2004). Interestingly, we also observed extensive keratin depletion in 16E1^E4-positive cells in HPV16-infected cervical tissue and in HPV16 organotypic raft tissue ( Fig.…”

Section: Discussionsupporting

confidence: 61%

“…Accumulation of E1^E4 coincides with the onset of viral-genome amplification, but precedes the expression of the viral structural proteins (L1 and L2) (Doorbar et al, 1997;Middleton et al, 2003;Peh et al, 2004). The E1^E4 proteins of HPV1 and HPV16 have been shown to associate with the keratin intermediate filament (IF) network in cultured cells (Doorbar et al, 1991;Roberts et al, 1993). The binding of HPV16 E1^E4 (16E1^E4), via an N-terminal leucine-rich motif ('LLKLL'), to keratin and subsequent E1^E4 multimerisation, mediated by a C-terminal multimerisation domain, has been shown to result in reorganisation of keratin IF networks (Roberts et al, 1994;Roberts et al, 1997;Wang et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

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E1^E4-mediated keratin phosphorylation and ubiquitylation: a mechanism for keratin depletion in HPV16-infected epithelium

McIntosh¹,

Laskey²,

Sullivan³

et al. 2010

Journal of Cell Science

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SummaryThe keratin IF network of epidermal keratinocytes provides a protective barrier against mechanical insult, it is also a major player in absorbing stress in these cells. The human papilloma virus (HPV) type 16 E1^E4 protein accumulates in the upper layers of HPV16-infected epithelium and is known to associate with and reorganise the keratin IF network in cells in culture. Here, we show that this function is conserved amongst a number of HPV alpha-group E1^E4 proteins and that the differentiation-dependent keratins are also targeted. Using time-lapse microscopy, HPV16 E1^E4 was found to effect a dramatic cessation of keratin IF network dynamics by associating with both soluble and insoluble keratin. Network disruption was accompanied by keratin hyperphosphorylation at several sites, including K8 S73, which is typically phosphorylated in response to stress stimuli. Keratin immunoprecipitated from E1^E4-expressing cells was also found to be ubiquitylated, indicating that it is targeted for proteasomal degradation. Interestingly, the accumulation of hyperphosphorylated, ubiquitylated E1^E4-keratin structures was found to result in an impairment of proteasomal function. These observations shed new light on the mechanism of keratin IF network reorganisation mediated by HPV16 E1^E4 and provide an insight into the depletion of keratin co-incident with E1^E4 accumulation observed in HPV-infected epithelium.

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Section: Discussionsupporting

confidence: 61%

Section: Introductionmentioning

confidence: 99%

E1^E4-mediated keratin phosphorylation and ubiquitylation: a mechanism for keratin depletion in HPV16-infected epithelium

McIntosh¹,

Laskey²,

Sullivan³

et al. 2010

Journal of Cell Science

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“…In some cases, the association results in reorganisation of the cytoskeleton. Whether this interaction may help the replication of the virus in vivo is still to be clarified [49,108].…”

Section: The Virus: Structure Genome and Control Of Transcriptionmentioning

confidence: 99%

Bovine papillomaviruses, papillomas and cancer in cattle

Borzacchiello¹,

Roperto²

2008

Vet. Res.

173

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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“…The E4 protein causes dramatic changes in the cytokeratin network altering the cytoplasmic environment of spinous cells, which contributes to the HPV induced cytopathic effect and koilocytosis [12][13][14]. These changes accelerate the release of virions assembled due to self-aggregation of the L1/L2 protein complexes.…”

Section: Skin Infectionmentioning

confidence: 99%

Diagnostic role of p16/INK4A protein in Human Papillomavirus (HPV) induced cervical dysplasia

Rajčáni¹,

Adamkov²,

et al. 2010

Open Life Sciences

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Abstract:The p16/INK4A protein is a cellular regulatory polypeptide over-expressed in the presence of high levels of the Human Papillomavirus (HPV) coded E7 protein. This review outlines the use of p16 antigen staining in cervical biopsies as well as in PAP smears summarizing the corresponding literature and commenting the authors' own experience. The p16 antigen is a reliable marker for dysplastic cells in CINII/CINIII (HSIL) lesions as viewed in cervical biopsies. When PAP smears were examined at large scale screening for p16 antigenreactive and atypical cells, considerable variations could be found especially in ASCUS graded lesions. Therefore, the presence of p16-reactive atypical cells in PAP smears should be interpreted together with the cytological signs of dysplasia, such as the altered N/C ratio. In addition, women revealing p16-positive ASCUS/LSIL specimens should be examined for the presence of HPV DNA. Detection of HPV DNA alone, i.e. in the absence of cytological screening has a low predictive value, since the clearance of HPV may occur even in the absence of morphological alterations. Combined cytological as well as molecular follow up contributes to the efficiency of diagnostic and increases the probability of correct interpretation of the pre-cancerous lesions by non-invasive techniques.

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Cutaneous and Mucosal Human Papillomavirus E4 Proteins Form Intermediate Filament-like Structures in Epithelial Cells

Cited by 69 publications

References 0 publications

E1^E4-mediated keratin phosphorylation and ubiquitylation: a mechanism for keratin depletion in HPV16-infected epithelium

E1^E4-mediated keratin phosphorylation and ubiquitylation: a mechanism for keratin depletion in HPV16-infected epithelium

Bovine papillomaviruses, papillomas and cancer in cattle

Diagnostic role of p16/INK4A protein in Human Papillomavirus (HPV) induced cervical dysplasia

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