Transforming functions of Simian Virus 40

Sáenz-Robles, Maria Teresa; Sullivan, Christopher S.; Pipas, James M.

doi:10.1038/sj.onc.1204936

Cited by 93 publications

(79 citation statements)

References 89 publications

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“…To address this possibility, we analyzed the expression levels of p53 in islets and tumors by immunohistochemistry and found that the heterogeneity of Tag protein levels seemed to partly correlate with the levels of p53 protein in the b cells (Figure 1, top three panels), consistent with previous studies in this model (Efrat et al, 1987). This result is also consistent with other studies that have shown Tag binding to p53 both inhibits p53 function while increasing abundance of p53 protein by limiting its MDM2-dependent degradation (Pipas and Levine, 2001;Saenz-Robles et al, 2001). In addition, Tag protein levels vary similarly with the PCNA and Ki67 proliferation markers as revealed by immunofluorescence ( Figure 1, three bottom panels and data not shown), suggesting that a threshold level of the T antigen oncoprotein may be deterministic for the state of b-cell hyperproliferation.…”

Section: Resultssupporting

confidence: 82%

Incomplete inhibition of the Rb tumor suppressor pathway in the context of inactivated p53 is sufficient for pancreatic islet tumorigenesis

et al. 2005

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Here, we describe the surprising residual capability of the Rb pathway to negatively regulate proliferation and tumorigenesis in a SV40 large T antigen (Tag)-driven mouse model of pancreatic islet carcinogenesis. Heterogeneous Tag expression during all progression stages suggested that a threshold level of the T antigen oncoprotein might be deterministic for b-cell hyperproliferation and led us to hypothesize that Tag might not be fully inhibiting the tumor suppressor activity of Rb. Moreover, genomic profiling of these tumors by array CGH pointed to regions of loss on chromosomes 6 and 14, where the Rb pathway inhibitor p27 and Rb itself, respectively, reside. Indeed, genetic ablation of the p27 Kip1 or Rb genes accentuated Tag-induced tumorigenesis, with loss of Rb in particular broadly enhancing multiple parameters of tumorigenesis including the frequency and growth rates of premalignant lesions, of nascent solid tumors, and of invasive carcinomas. The data indicate that attenuation rather than complete inactivation of Rb tumor suppressor gene function, in the context of p53 inhibition, is sufficient to initiate tumorigenesis in this model of islet cell cancer, with the demonstrable possibility that subsequent losses of Rb or its regulators can enhance malignant progression. The results may be relevant to human papillomavirus (HPV)-induced cervical neoplasias where E7 oncogene expression levels or activity (in the case of intermediate/low-risk HPV subtypes) incompletely inhibits Rb tumor suppressor functions, as well as to other neoplasias where initiating oncogenic or tumor suppressor events reduce but do not abrogate Rb function.

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Section: Resultssupporting

confidence: 82%

Incomplete inhibition of the Rb tumor suppressor pathway in the context of inactivated p53 is sufficient for pancreatic islet tumorigenesis

et al. 2005

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“…This viral oncogene acts as a dominant transforming protein that targets cellular proteins and thereby alters the cell's growth properties (23). In particular, the inactivation of p53 and the pRB family members is required for cell transformation.…”

Section: Discussionmentioning

confidence: 99%

Simian Virus 40 Large T Antigen's Association with the CUL7 SCF Complex Contributes to Cellular Transformation

Kasper

Kuwabara

Arai

et al. 2005

J Virol

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Simian virus 40 large T antigen (T Ag) is capable of immortalizing and transforming rodent cells. The transforming activity of T Ag is due in large part to perturbation of the tumor suppressor proteins p53 and the retinoblastoma (pRB) family members. Inactivation of these tumor suppressors may not be sufficient for T Ag-mediated cellular transformation. It has been shown that T Ag associates with an SCF-like complex that contains a member of the cullin family of E3 ubiquitin ligases, CUL7, as well as SKP1, RBX1, and an F-box protein, FBXW8. We identified T Ag residues 69 to 83 as required for T Ag binding to the CUL7 complex. We demonstrate that ⌬69-83 T Ag, while it lost its ability to associate with CUL7, retained binding to p53 and pRB family members. In the presence of CUL7, wild-type (WT) T Ag but not ⌬69-83 T Ag was able to induce proliferation of mouse embryo fibroblasts, an indication of cellular transformation. In contrast, WT and ⌬69-83 T Ag enabled mouse embryo fibroblasts to proliferate to similarly high densities in the absence of CUL7. Our data suggest that, in addition to p53 and the pRB family members, T Ag serves to bind to and inactivate the growth-suppressing properties of CUL7. In addition, these results imply that, at least in the presence of T Ag, CUL7 may function as a tumor suppressor.Simian virus 40 (SV40) is well characterized as a tool to study neoplastic transformation and cell cycle regulation. Two tumor antigens are encoded by SV40: large T antigen (T Ag) and small t antigen (t ag). Both are expressed from a differentially spliced common precursor mRNA, and their expression occurs soon after infection from a transcript initiating at the early promoter. T Ag is a 708-amino-acid protein that plays a major role in viral replication, in part by driving entry into the cell cycle of quiescent cells. In addition to its critical roles in establishing productive infection, T Ag is required for viral tumorigenesis. The transforming activity of T Ag is due in large part to its perturbation of the retinoblastoma (pRB) family members and p53 tumor suppressor proteins (12,32).The p53 protein is a key regulator of the cell cycle in response to a variety of cellular stresses, and the gene encoding p53 is mutated in the majority of human tumors. The activities of p53 are mediated largely by its ability to transcriptionally regulate genes that either induce cell cycle arrest (e.g., Cdkn1a) or promote apoptosis (e.g., Bax). Through this transcriptional regulation, p53 plays an essential role in the maintenance of genomic integrity (20). Two carboxy-terminal regions of T Ag, residues 351 to 450 and 533 to 626, are required for its direct association with this tumor suppressor (12,15,33). It is well known that T Ag inactivation of the tumorsuppressing function of p53 contributes significantly to the ability of T Ag to induce entry into the cell cycle and proliferation, ultimately leading to a transformed phenotype.Another primary transforming function of T Ag is the inactivation of pRB family members. P...

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“…By SV40 transfection of early-passage primary cells, we generated an immortalised islet MEC line that has a longer life span than that of primary cells, with a continuous period of vigorous growth. It is known that SV40 large T-Ag can induce immortalisation of the cells by interfering with several pathways related to cell cycle control through the binding and blockade of tumour suppressor proteins such as p53, pRb, p107, and p130/Rb2 [43,45]. In the present study, over 90% of the cells of the immortalised islet MEC line were positive for nuclear staining specific to SV40 large T-Ag, and molecular evidence indicated that the complete gene sequence was present in cultured cells.…”

Section: Discussionmentioning

confidence: 99%

Primary and immortalised human pancreatic islet endothelial cells: phenotypic and immunological characterisation

et al. 2005

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Aims/hypothesis: Studies on the biology of the microvascular endothelial cells (MECs) that surround and penetrate the pancreatic islets are hampered by difficulties in isolating and culturing large numbers of pure cells. We aimed to morphologically and functionally characterise primary MECs purified and cultured from human islets, and to establish a simian virus 40 (SV40)-immortalised cell line from these primary cultures. Materials and methods: Human islet MECs were extracted and purified using anti-CD105 coated immunomagnetic beads, and endothelial markers and surface molecules analysed by flow cytometric analysis. An immortalised cell line was then established by using a chimeric adeno5/SV40 virus. Results: Islet MECs expressed classic and specific endothelial markers, a high basal level of intercellular adhesion molecule-1, and low levels of E-selectin and TNF (previously known as TNF-α) inducible vascular cell adhesion molecule-1. IFNG (previously known as IFN-γ) induced expression of HLA class II molecules. The immortalised islet MECs expanded rapidly, exhibited increased DNA synthesis, and were passaged approximately 30 times, without signs of senescence. They retained the endothelial characteristics of the parental cells, and behaved as the primary cells in terms of TNF stimulation of expression of adhesion molecules and support of leucocyte adhesion and transmigration. Conclusions/interpretation: The immortalised islet MECs that we have established could effectively represent a substitute for primary counterparts for in vitro studies on the role of the microvasculature in pathophysiological processes involved in type 1 and type 2 diabetes.

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Transforming functions of Simian Virus 40

Cited by 93 publications

References 89 publications

Incomplete inhibition of the Rb tumor suppressor pathway in the context of inactivated p53 is sufficient for pancreatic islet tumorigenesis

Incomplete inhibition of the Rb tumor suppressor pathway in the context of inactivated p53 is sufficient for pancreatic islet tumorigenesis

Simian Virus 40 Large T Antigen's Association with the CUL7 SCF Complex Contributes to Cellular Transformation

Primary and immortalised human pancreatic islet endothelial cells: phenotypic and immunological characterisation

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