The bovine papillomavirus E5 transforming protein can stimulate the transforming activity of EGF and CSF-1 receptors

Martin, Patrick; Vass, William C.; Schiller, John T.; Lowy, Douglas R.; Velu, Thierry

doi:10.1016/0092-8674(89)90866-0

Cited by 167 publications

(123 citation statements)

References 47 publications

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“…BPV-1 E5 can transform established mouse ®broblasts (Settleman et al, 1989) and keratinocytes (Leptak et al, 1991). The transforming function of E5 is attributed to its ability to activate growth factor receptors (Martin et al, 1989;Goldstein et al, 1994) and to complex with 16 kDa ductin, a component of both the vacuolar ATPase and gap junctions (Goldstein et al, 1991). It has been suggested that E5 acts to potentiate mitogenic signals from growth factors and to reduce homeostatic control on virally infected cells exerted by surrounding normal cells (Jackson et al, 1996).…”

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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“…The BPV-1 E5 protein is the primary transforming protein in bovine papillomaviruses (BPV), functioning through cellular growth factor receptors like the platelet-derived growth factor (PDGFR) (Petti et al, 1991) and in transient assays with the eipdermal growth factor receptor (EGFP) (Martin et al, 1989). In contrast to BPV E5, the HPV E5 protein exhibits only weak transforming activity (Leechanachai et al, 1992;Bouvard et al, 1994;Valle and Banks, 1995).…”

Section: Activities Of the High-risk Hpv E5 Proteinmentioning

confidence: 99%

Human papillomaviruses: targeting differentiating epithelial cells for malignant transformation

2003

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Human papillomavirus (HPV) infections play a crucial role in the pathogenesis of cervical neoplasia. Insights into the mechanisms by which HPV infection can, in a small numbers of cases, result in malignancy, comes from the observation that three proteins encoded by high-risk genital HPVs, E6, E7 and to a lesser extent E5, target factors that control the cell cycle and proliferation. These interactions result in abrogation of cell cycle control, chromosomal alterations, telomerase activation, and eventual cell immortalization. In this review, we discuss the functions of E6, E7, and E5 proteins that are most relevant to the malignant progression of HPV-transformed cells.

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“…Two ®ndings suggested that growth factor receptors were targets of the BPV E5 protein. First, the E5 gene displayed increased focus forming activity in NIH3T3 cells when it was co-transfected with genes encoding receptor tyrosine kinases (RTKs) (Martin et al, 1989). Second, acute expression of the BPV E5 protein, like treatment with serum or puri®ed growth factors, induced quiescent ®broblasts to commence DNA synthesis (Settleman et al, 1989).…”

Section: Bovine Papillomavirus E5 Proteinmentioning

confidence: 99%

Mechanisms of cell transformation by papillomavirus E5 proteins

2001

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The papillomavirus E5 proteins are short, hydrophobic transforming proteins. The transmembrane E5 protein encoded by bovine papillomavirus transforms cells by activating the platelet-derived growth factor b receptor tyrosine kinase in a ligand-independent fashion. The bovine papillomavirus E5 protein forms a stable complex with the receptor, thereby inducing receptor dimerization and activation, trans-phosphorylation, and recruitment of cellular signaling proteins to the receptor. The E5 proteins of the human papillomaviruses also appear to a ect the activity of growth factor receptors and their signaling pathways. The interaction of papillomavirus E5 proteins with a subunit of the vacuolar ATPase may also contribute to transformation. Further analysis of these unique mechanisms of viral transformation will yield new insight into the regulation of growth factor receptor activity and cellular signal transduction pathways. Oncogene (2001) 20, 7866 ± 7873.

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The bovine papillomavirus E5 transforming protein can stimulate the transforming activity of EGF and CSF-1 receptors

Cited by 167 publications

References 47 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

Human papillomaviruses: targeting differentiating epithelial cells for malignant transformation

Mechanisms of cell transformation by papillomavirus E5 proteins

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