Analysis of the Transforming Functions of Bovine Papillomavirus Type 4

Wd, Pennie; Gj, Grindlay; Cairney, M.; Ms, Campo

doi:10.1006/viro.1993.1169

Cited by 48 publications

(70 citation statements)

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“…We have demonstrated previously that the E8 ORF can confer AI growth on primary bovine ®broblasts co-expressing BPV-4 E7 and an activated ras gene (Pennie et al, 1993). We found that E8-3T3 cells were also capable of AI growth (Figure 2a) with an e ciency of colony formation (diameter 40.1 mm) approximately 3.5 times that of parental or control cells ( Figure 2b); large (40.25 mm) colonies were found only in cells expressing E8.…”

Section: Resultsmentioning

confidence: 99%

“…The expression plasmid for E8 ORF (pZipneoE8) has been described previously (Pennie et al, 1993) and the form of E8 in which a premature stop codon has been introduced at residue 31 (E8N1-30) will be described in O'Brien et al…”

Section: Plasmidsmentioning

confidence: 99%

“…It is not yet known if E8 can interact with growth factor receptors to promote their activation. E8 also contributes to cell transformation by allowing cells to proliferate in suspension (Pennie et al, 1993), demonstrating that it over-rides the control mechanisms that arrest anchorage-dependent cells in late G1 phase of the cell cycle when maintained in suspension (Guadagno and Assoian, 1991).…”

Section: Introductionmentioning

confidence: 99%

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BPV-4 E8 transforms NIH3T3 cells, up-regulates cyclin A and cyclin A-associated kinase activity and de-regulates expression of the cdk inhibitor p27Kip1

O'Brien

Campo

1998

Oncogene

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The E8 open reading frame of Bovine papillomavirus type 4 (BPV-4) encodes a small (42 amino acid) hydrophobic polypeptide localized to cellular membranes and capable of conferring an anchorage-independent (AI) growth phenotype on primary bovine cells co-transfected with BPV-4 E7 ORF and an activated ras gene. To further study the function of E8 independently of other viral gene products, we have expressed it in the murine ®broblast cell line, NIH3T3. Cells expressing E8 are capable of AI growth and escape growth arrest after serum withdrawal. E8 deregulates cyclin A expression, induces transactivation of the human cyclin A gene promoter and increases endogenous protein levels in cells maintained in short-term suspension culture and in lowserum (LS). Both these culture conditions promote downregulation of cyclin A in control cells. In LS growth conditions E8 permits sustained cyclin A-associated kinase activity but not cyclin E-cdk2 activity. Cyclin A-cdk2 activity and, in part, cyclin A gene expression are regulated by the cdk inhibitor p27 Kip1 . Expression of this cdk inhibitor is also de-regulated in E8 cells, with high levels being detected under all culture conditions tested. These data suggest that the ability of BPV-4 E8 to transform NIH3T3 cells is associated with upregulation of cyclin A-associated kinase activity and de-regulated expression of the cdk inhibitor p27 Kip1 and does not rely on down-regulation of p27 Kip1 expression. Analysis of E8 mutants indicate that the hydrophilic tail' of the molecule (residues 31 ± 42) is required for cell transformation, as assessed by anchorage-independent growth, while a form of E8 with expression restricted to the Endoplasmic Reticulum/cis-Golgi membranes by addition of a`KDEL' retention signal revealed that the sub-cellular localization is an important determinant of E8 biological activity.

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Section: Resultsmentioning

confidence: 99%

Section: Plasmidsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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BPV-4 E8 transforms NIH3T3 cells, up-regulates cyclin A and cyclin A-associated kinase activity and de-regulates expression of the cdk inhibitor p27Kip1

O'Brien

Campo

1998

Oncogene

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“…BPV-4 transformed cells are not contact inhibited, can grow in low serum and in suspension (V O'Brien et al, in preparation; Pennie et al, 1993) but are not immortal or tumorigenic in nude mice (Jaggar et al, 1990;Pennie et al, 1993). Exposure of BPV-4 transformed cells to a single dose of quercetin results in immortalisation and oncogenic progression (Pennie and Campo, 1992;Cairney and Campo, 1995), strengthening the hypothesis that quercetin is one of the co-carcinogens in vivo.…”

Section: Introductionmentioning

confidence: 91%

The BPV-4 co-carcinogen quercetin induces cell cycle arrest and up-regulates transcription from the LCR of BPV-4

et al. 1998

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Bracken fern is the environmental co-carcinogen of BPV-4 in the induction of neoplasias of the upper alimentary canal of cattle. The¯avonoid quercetin is one of the most potent and best characterised mutagens present in the fern. We have shown that transfection with BPV-4 DNA and exposure to a single dose of quercetin leads to tumorigenic transformation of primary bovine cells. We now show that quercetin induces cell cycle arrest and up-regulates transcription from the BPV-4 long control region (LCR). This up-regulation is mediated by a 21 nucleotide-long cis-element in the LCR, designated QRE-1, which is located immediately downstream of the TATA box. Cellular proteins bind to QRE-1 and removal or substitution of QRE-1 lead to the abrogation of the response to quercetin. As expression of the viral oncogenes is controlled by the LCR, perturbation in this control and increased oncoprotein expression are likely to contribute to fully malignant cell transformation by overcoming the cell cycle arrest induced by quercetin, thus forcing damaged cells to proliferate.

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“…BPV-4 E5 has a hydrophobic N-terminal region (residues 1-30) with a putative a-helix conformation and a hydrophilic C-terminal tail of 12 residues (Jackson et al, 1991). It transforms established NIH 3T3 cells and primary bovine fibroblasts (PalF) (which coexpress BPV-4 E7 and an activated Ras), allowing cell growth in low serum (LS) concentrations and in suspension (O'Brien & Campo, 1998;O'Brien et al, 1999;Pennie et al, 1993). E5-transformed NIH 3T3 cells have an elevated pool of cyclin D1/CDK4 complexes that retain their kinase activity, despite being associated with a high level of the CDK inhibitor p27 KIP1 (p27) under normal growth conditions or in the absence of mitogens (O'Brien et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Cyclin A expression and growth in suspension can be uncoupled from p27 deregulation and extracellular signal-regulated kinase activity in cells transformed by bovine papillomavirus type 4 E5

Zago

Campo

O'Brien

2004

Journal of General Virology

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As the biochemical detection of bovine papillomavirus type 4 E5 is problematic, a fusion form of E5 and the green fluorescent protein (GFP-E5) was constructed and its characteristics were examined. GFP-E5 was detected in cells by autofluorescence and immunoblotting. Like wild-type (wt) E5, GFP-E5 localized in the endomembranes and permitted anchorage-independent (AI) growth. However, unlike wt E5, cells expressing GFP-E5 became quiescent in low serum and failed to sustain expression of cyclins D1 and to inactivate retinoblastoma protein (pRb). The normal anchorage requirement for cyclin D1 and cyclin A expression was abolished in cells expressing wt E5 or GFP-E5, residual extracellular signal-regulated kinase (ERK 1/2) activity was not required to sustain cyclin D1 and cyclin A expression in suspension and deregulation of cyclin A-cyclin-dependent kinase (CDK) activity was sufficient to account for AI growth of cells expressing E5. Constitutive upregulation of the CDK inhibitor p27 KIP1 , characteristic of cells expressing wt E5, was not observed in those expressing GFP-E5; therefore, p27 KIP1 deregulation is not required for E5-mediated AI growth.

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Analysis of the Transforming Functions of Bovine Papillomavirus Type 4

Cited by 48 publications

References 0 publications

BPV-4 E8 transforms NIH3T3 cells, up-regulates cyclin A and cyclin A-associated kinase activity and de-regulates expression of the cdk inhibitor p27Kip1

BPV-4 E8 transforms NIH3T3 cells, up-regulates cyclin A and cyclin A-associated kinase activity and de-regulates expression of the cdk inhibitor p27Kip1

The BPV-4 co-carcinogen quercetin induces cell cycle arrest and up-regulates transcription from the LCR of BPV-4

Cyclin A expression and growth in suspension can be uncoupled from p27 deregulation and extracellular signal-regulated kinase activity in cells transformed by bovine papillomavirus type 4 E5

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