Cooperation Between Bovine Papillomavirus Type 4 and ras in the Morphological Transformation of Primary Bovine Fibroblasts

Jaggar, Rhys T.; Pennie, William D.; Smith, K. T.; Jackson, M. E.; Campo, M. Saveria

doi:10.1099/0022-1317-71-12-3041

Cited by 31 publications

(32 citation statements)

References 23 publications

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“…BPV-4 is incapable of transforming bovine primary ®broblasts derived from the foetal palate (PalFs), requiring, instead, cooperation with an activated ras gene. These partially transformed PalFs have an extended proliferative life-span, are capable of anchorage-independent (AI) growth but are not tumorigenic in athymic mice (Jaggar et al, 1990).…”

Section: Introductionmentioning

confidence: 99%

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: Introductionmentioning

confidence: 99%

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: 90%

“…As it is known that even a moderate increase in the expression of the viral oncogenes leads to enhanced cell transformation (Jaggar et al, 1990), we tested whether quercetin can upregulate the transcriptional activity of the viral long control region (LCR). The full length LCR (nt 6710-331; Figure 2) was cloned into the luciferase reporter vector pGL3 and its ability to drive expression of the luciferase gene was examined in PalF cells treated with quercetin or with its solvent ethanol.…”

Section: Quercetin Up-regulates the Viral Long Control Regionmentioning

confidence: 99%

“…The isolation of ®broblasts from foetal bovine palate was as described previously by Jaggar et al (1990). Brie¯y, a small section of palate tissue was taken from a bovine foetus at no more than 5 months gestation.…”

Section: Cell Culture Of Primary Bovine ®Broblasts (Palf)mentioning

confidence: 99%

“…We show that quercetin induces cell cycle arrest in both G1 and G2 and that it induces a modest but noticeable and reproducible up-regulation of the LCR, in the same conditions in which it promotes malignant transformation. These two events are likely to play a role in the observed synergism: even a small increase in the expression of the viral oncogenes results in a greater degree of cell transformation (Smith et al, 1987;Jaggar et al, 1990), and increased viral oncoprotein expression could force quercetin-arrested cells to proliferate, thus any genetic damage induced by the¯avonoid would be inherited by progeny cells.…”

Section: Introductionmentioning

confidence: 99%

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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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Transforming Proteins of Human Papillomaviruses

Ullman

Emery

1996

Rev. Med. Virol.

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Cooperation Between Bovine Papillomavirus Type 4 and ras in the Morphological Transformation of Primary Bovine Fibroblasts

Cited by 31 publications

References 23 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

Transforming Proteins of Human Papillomaviruses

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