Differential Sensitivity of Mouse Epithelial Tissues to the Polyomavirus Middle T Oncogene

Ceceña, G; Wen, Fang; Cardiff, Robert D.; Oshima, Robert G.

doi:10.2353/ajpath.2006.050443

Cited by 13 publications

(11 citation statements)

References 32 publications

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“…Although SHC binding is important for MT-mediated transformation of rodent cells, activation of the MAPK pathway is rarely, if ever, seen in cell lines stably expressing wild-type MT, even though transient expression of MT can indeed activate the MAPK pathway via SHC (48) and MAPK activation is seen in MT-induced tumors in vivo (5). It has always been presumed that some feedback loop or cross-talk from another pathway was inhibiting MAPK activation.…”

Section: Discussionmentioning

confidence: 99%

The p110α Isoform of Phosphatidylinositol 3-Kinase Is Essential for Polyomavirus Middle T Antigen-Mediated Transformation

Utermark

Schaffhausen

Roberts

et al. 2007

J Virol

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Middle T antigen (MT) of polyomavirus is known to play an important role in virus-mediated cellular transformation. While MT has been extensively examined in spontaneously immortalized rodent fibroblasts, its interactions with cells of other types and species are less well understood. We have undertaken a cross-species and cross-cell-type comparison of MT-induced transformation in cells with genetically defined backgrounds. We tested the transforming abilities of a panel of MT mutants, Y250F, Y315F, and Y322F, that are selectively mutated in the binding sites for the principal effectors of MT-Src homology 2 domain-containing transforming protein, phosphatidylinositol 3-kinase (PI3K), and phospholipase C-␥, respectively-in fibroblasts and epithelial cells of murine or human origin. We found that the Y315F mutation disabled the ability of MT to induce transformation in all cell types and species tested. While Y315F also failed to activate the PI3K pathway in these cells, genetic evidence has indicated Y315 may make other contributions to transformation. To confirm the role of PI3K, the PIK3CA gene, encoding p110␣, the prime effector of PI3K signaling downstream from activated growth factor receptors, was genetically ablated. This abolished the transforming activity of MT, demonstrating the essential role for this PI3K isoform in MT-mediated transformation. The Y250F mutant was able to transform the human, but not the murine, cells that were examined. Interestingly, this mutant fully activates the PI3K pathway in human cells but activated PI3K signaling poorly in the murine cells used in the study. This again points to the importance of PI3K activation for transformation and suggests that the mechanism by which MT activates the PI3K pathway differs in different species.Polyomavirus (PyV) is a small, double-stranded, closed-circular-DNA virus with an approximately 5-kb genome divided into two roughly equal regions. The late transcripts produce the viral capsid proteins, whereas the early region encodes three so-called tumor (T) antigens (46) that are important for both productive infection and transformation. The 785-aminoacid large T antigen (LT) is a nuclear protein with originspecific DNA binding properties and an ATPase activity essential for viral replication (46). LT cannot transform cells in culture but has the ability to immortalize primary cells (16,32). Small t antigen (st) is a 195-amino-acid protein found both in the nucleus and in the cytoplasm (46). It is known to bind and thereby inhibit protein phosphatase 2A (PP2A) (39, 52). Middle T antigen (MT), a 421-amino-acid protein associated with membranes and underlying cytoskeletal elements, has been shown to be essential for transformation of rodent fibroblasts in tissue cultures (20,34,47). Mammary epithelial cell-specific expression of MT in transgenic mice results in the induction of multifocal mammary tumors with 100% penetrance (21).MT functions by providing a platform for the assembly of cellular signaling proteins (11,26). Like st, it binds to the ...

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Section: Discussionmentioning

confidence: 99%

The p110α Isoform of Phosphatidylinositol 3-Kinase Is Essential for Polyomavirus Middle T Antigen-Mediated Transformation

Utermark

Schaffhausen

Roberts

et al. 2007

J Virol

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“…However, this promoter also drives gene expression in other tissues, causing other types of cancers in various organs, which limited its usefulness in prostate cancer studies. The second system utilized the LoxP-stop-LoxP cassette system to limit the expression of an MT transgene to only those tissues in which cre was expressed via either a second transgene or a viral vector (7). Upon deletion of the stopper sequences through cre recombinase expression (Probasin-Cre) in the prostate, MT expression was induced, again ultimately resulting in mPIN.…”

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confidence: 99%

Transgenic Expression of Polyomavirus Middle T Antigen in the Mouse Prostate Gives Rise to Carcinoma

Lee

Jia

Zhu

et al. 2011

J Virol

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The middle T (MT) antigen of polyomavirus has provided fundamental insights into the regulation of mammalian cell growth in vitro and important animal models for the analysis of tumor induction. The mouse mammary tumor virus (MMTV)-MT model of breast cancer has been important for probing the cellular signaling pathways in mammary tumorigenesis. MT itself has no intrinsic enzymatic activity but, rather, transforms by binding to and activating key intracellular signaling molecules, phosphatidylinositol 3-kinase (PI3-kinase) being the best studied of these. Thus, MT mimics a constitutively activated receptor tyrosine kinase (RTK). Our recent work suggests that MT signaling, like that of RTKs, is often quite dependent on cellular context in vitro. Here, we examine contextual effects on signaling in animal models as well. In this study, we generated transgenic mice in which MT is expressed in the mouse prostate under the control of an (ARR)2-Probasin promoter. All male transgenic mice displayed mouse prostatic intraepithelial neoplasia In the male population of the United States, prostate cancer is the second most commonly diagnosed cancer after dermatologic cancer. Typically developing slowly with age, it ranks second among all cancers as a cause of mortality in men in the United States. Considerable insight concerning the effects of genetic alterations on prostate tissue has been gleaned from a number of genetically engineered mouse models (GEMs). For example, the activation of receptor tyrosine kinase (RTK) pathways has been modeled via transgenic mice expressing Fgf8b (15, 56), Neu (34), and Erbb2 (6). Loss-of-function models for tumor suppressor genes include Nkx3.1 (30) and PTEN (11,61,63,68). Models of oncogene expression include the expression of Akt (40), PIK3CB (32), c-myc (14), H-ras (52), and two models expressing simian virus 40 (SV40) large T antigen (the transgenic adenocarcinoma of mouse prostate [TRAMP] model [22] and the large probasin-large T antigen [LPB-Tag] model [41]). The resulting lesions vary according to the target gene, displaying histological abnormalities ranging from hyperplasia to metastatic cancer. Tumor development in most transgenic mice created via the expression of a single gene is limited to hyperplasia or mouse prostatic intraepithelial neoplasia (mPIN), while high levels of expression of myc and SV40 T antigen resulted in metastatic cancers (14,22). Gene deletion of Nkx3.1 or PTEN did not result in metastatic adenocarcinoma (11,30,61,63) except in one PTEN study (68). However, double knockout models, such as the deletion of PTEN together with p53 (9), p27 (10), or Nkx3.1 (31), develop more aggressive phenotypes, suggesting that multiple genetic hits may be required to accelerate prostate cancer progression initiated by PTEN loss.Polyomavirus (PyV) middle T antigen (MT) is one of three early gene products encoded by the single early mRNA of this small DNA tumor virus (21, 51). It is the only protein encoded by the PyV genome that induces transformation in vitro. MT utilizes a hy...

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“…In a recent study, Cecena et al (2006) used an elegant Cre-dependent expression system to generate conditional PyMT expression in transgenic mice. The PyMT gene was attached to a loxP-disabled keratin-18 (K18) promoter.…”

Section: Discussionmentioning

confidence: 99%

Mice transgenic with SV40-late-promoter-driven Polyomavirus Middle T oncogene exclusively develop hemangiomas

Chen

Wang

et al. 2008

Transgenic Res

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In order to develop a model system of infantile hemangioma, transgenic mice were developed carrying the Polyomavirus Middle T (PyMT) gene driven by the SV40 late promoter. From the 520 fertilized eggs surviving microinjection, there were 25 live births. Three of these showed the hemangioma phenotype and carried and expressed the PyMT gene; the remaining descendants were normal. The tumors showed abnormal vascular proliferation with cavernous hemangioma-like structures in the skin surface, tongue, ear mucosa and gastric mucosal tissue in the transgenic mice with hemangioma phenotype. Immunohistochemical staining for Ki-67 was negative, showing the tumors were hemangiomas rather than angiosarcomas. None of the PyMT transgenic mice survived beyond 4 weeks. Previously reported PyMT transgenic mice under the control of various promoters induce many tumor types including hemangiomas. PyMT driven by the SV40 late promoter is an improved model system because it only induces hemangiomas. However, it is limited by the post-natal lethality. Thus, conditional variants of this model system would be desirable.

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Differential Sensitivity of Mouse Epithelial Tissues to the Polyomavirus Middle T Oncogene

Cited by 13 publications

References 32 publications

The p110α Isoform of Phosphatidylinositol 3-Kinase Is Essential for Polyomavirus Middle T Antigen-Mediated Transformation

The p110α Isoform of Phosphatidylinositol 3-Kinase Is Essential for Polyomavirus Middle T Antigen-Mediated Transformation

Transgenic Expression of Polyomavirus Middle T Antigen in the Mouse Prostate Gives Rise to Carcinoma

Mice transgenic with SV40-late-promoter-driven Polyomavirus Middle T oncogene exclusively develop hemangiomas

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