Natural Biology of Polyomavirus Middle T Antigen

Gottlieb, Keith; Villarreal, Luis P.

doi:10.1128/mmbr.65.2.288-318.2001

Cited by 48 publications

(35 citation statements)

References 393 publications

(403 reference statements)

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“…3A). We then assayed the activation state of the Akt and Erk kinases, which are known to act downstream of PyMT-mediated signaling pathways (13). Western blot analysis showed that both Akt and Erk are more highly phosphorylated, and presumably more active, in tumors than in normal tissue (Fig.…”

Section: Resultsmentioning

confidence: 99%

The Absence of p53 Promotes Metastasis in a Novel Somatic Mouse Model for Hepatocellular Carcinoma

Lewis

Klimstra²,

Socci

et al. 2005

Molecular and Cellular Biology

109

100

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We have generated a mouse model for hepatocellular carcinoma using somatic delivery of oncogene-bearing avian retroviral vectors to the liver cells of mice expressing the viral receptor TVA under the control of the albumin gene promoter (Alb-TVA mice). Viruses encoding mouse polyoma virus middle T antigen (PyMT) induced tumors, which can be visualized with magnetic resonance imaging, in 65% of TVA-positive animals. While these tumors can exceed 10 mm in diameter, they do not invade locally or metastasize to the lungs. Delivery of PyMT-expressing viruses to Alb-TVA mice lacking an intact p53 gene does not increase tumor incidence. However, the resulting tumors are poorly differentiated, invasive, and metastatic to the lungs. Gene expression microarrays identified over 100 genes that are differentially expressed between tumors found in p53 wild-type and p53 null mice. Some of these genes, such as cathepsin E and Igf2, have been previously implicated in tumor cell migration and invasion. Tumors induced in p53 null, TVA transgenic mice by PyMT mutants with changes in specific tyrosine residues fail to form metastases, indicating that metastasis is dependent on both the oncogene and the absence of p53.Hepatocellular carcinoma (HCC) exerts a significant toll on human health worldwide, with more than 250,000 new cases annually and a 5-year survival rate of less than 5% (36). Current treatment modalities are largely unsuccessful: single-agent and combination chemotherapy regimens have proven to be ineffective in the treatment of HCC patients (24). Therefore, surgery remains the only curative option for HCC; however, for most patients this is not a viable option because of significant liver cirrhosis or invasive and metastatic disease that has spread to the lymph nodes, portal vein, or lungs (20).HCC is strongly associated with chronic infection by hepatitis B virus (HBV) and hepatitis C virus (HCV): incidence of HCC correlates with HBV and HCV infection rates within a population, and the average age of onset is inversely correlated with the prevalence of HBV infection (4,39,45). Although the precise mechanisms by which HBV and HCV predispose to HCC are unclear, the current belief is that the liver damage and regeneration associated with chronic viral infection provide a context where oncogenic genetic alterations can occur and become fixed. The X protein encoded by HBV, through its regulation of calcium signaling that is critical for HBV replication, is thought to play an important role in this process (6). Other factors that predispose to the occurrence of HCC are prolonged exposure to aflatoxin B1, cirrhosis of any etiology, hemochromatosis, congenital hepatic fibrosis, and biliary atresia (22).Alterations in the TP53 gene are frequently found in HCC.Further, the absence of TP53 gene alterations in hepatic adenomas suggests that this is a late event in tumor progression (7). Silencing of the INK4A locus has also been observed in a majority of HCC patients (7,26,28). In addition, several chromosome arms-including 1p, 4...

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Section: Resultsmentioning

confidence: 99%

The Absence of p53 Promotes Metastasis in a Novel Somatic Mouse Model for Hepatocellular Carcinoma

Lewis

Klimstra²,

Socci

et al. 2005

Molecular and Cellular Biology

109

100

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“…The hydrophobic C-terminal region of PyMT required for its membrane binding (Gottlieb and Villarreal, 2001;Ichaso and Dilworth, 2001) is absent in both the PyMT8C and PyMT10C proteins. Thus it was of interest to determine the cellular location of these PyMT proteins in PyMT8C and PyMT10C cells.…”

Section: The Cellular Location Of the Pymt Mutant Proteinsmentioning

confidence: 99%

“…The loss of the ability of PyMT to bind to membranes is known to have an effect on transformation (Gottlieb and Villarreal, 2001;Ichaso and Dilworth, 2001) explaining the normal phenotype of REF52 cells containing the PyMT8C and PyMT10C mutant PyMT proteins. We find that the loss of the C-terminal PyMT region containing the hydrophobic region also affects the ability of PyMT to induce ARF.…”

Section: Pymt10c Retrovirusmentioning

confidence: 99%

“…These include PI3 kinase, PLC-gamma and the Ras-Raf-MAP Kinase pathway. The inappropriate activation of one or more of these cellular signaling pathways is thought to contribute to the oncogenic properties of PyMT (Gottlieb and Villarreal, 2001;Ichaso and Dilworth, 2001). PyMT induces ARF expression, which in turn activates p53, resulting in cell cycle arrest or apoptosis (Lomax and Fried, 2001;O'Shea and Fried, 2005).…”

Section: Introductionmentioning

confidence: 99%

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Chromosomal instability at a mutational hotspot in polyoma middle T-antigen affects its ability to activate the ARF-p53 tumor suppressor pathway

et al. 2005

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We have isolated spontaneous mutants of polyoma virus middle T-antigen (PyMT) that do not activate the ARFp53 pathway based on their inability to block REF52 cell division. The REF52 cells containing these mutants have a flat untransformed morphological phenotype and do not express the ARF protein. The PyMT mutations in the different cell isolates so far analysed occur at a mutational hotspot in the PyMT sequence between nucleotides 1241 and 1249, which contains nine consecutive cytosines. In one set of mutants a single cytosine was deleted, while in another mutant set an additional cytosine was inserted. Both these mutations result in frameshifts, generating altered PyMT proteins containing amino-acid sequences derived from each of the two other alternative reading frames of the polyoma virus early region. Both types of mutations result in the loss of the C-terminal PyMT region containing the membrane-binding hydrophobic region and result is mislocalization of the PyMT mutant proteins. Revertant wild-type PyMT (containing nine cytosines) was easily detected in transformants generated after infection of REF52 cells expressing high amounts of dominant negative p53 with retroviruses containing either mutation. We demonstrate that wild-type PyMT revertants are derived from mutations in the hotspot sequence of the integrated mutant PyMT sequences.

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“…The polyoma virus (Py) early region specifies three proteins, large T-antigen (PyLT), middle T-antigen (PyMT), and small T-antigen (PyST), by differential splicing of mRNA derived from the same genomic DNA sequence (1). The membrane-bound PyMT is a potent activating oncogene, which has no intrinsic enzyme activity but acts as a scaffolding protein and binds and modulates the activities of a number of important cellular signaling proteins (1,2). Studies with PyMT have provided great insight into a number of critical cellular signaling pathways involved in growth control (3).…”

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confidence: 99%

Polyoma and SV40 proteins differentially regulate PP2A to activate distinct cellular signaling pathways involved in growth control

Rodríguez‐Viciana

Collins

Fried

2006

Proc. Natl. Acad. Sci. U.S.A.

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Binding of Src family kinases to membrane-associated polyoma virus middle T-antigen (PyMT) can result in the phosphorylation of PyMT tyrosine 250, which serves as a docking site for the binding of Shc and subsequent activation of the Raf-MEK-ERK (MAP) kinase cascade. In a screen for PyMT variants that could not activate the ARF tumor suppressor, we isolated a cytoplasmic nontransforming mutant (MTA) that encoded a C-terminal truncated form of the PyMT protein. Surprisingly, MTA was able to strongly activate the MAP kinase pathway in the absence of Src family kinase and Shc binding. Interestingly, the polyoma small T-antigen (PyST), which shares with MTA both partial amino acid sequence homology and cellular location, also activates the MAP kinase cascade. Activation of the MAP kinase cascade by both MTA and PyST has been demonstrated to be PP2A-dependent. Neither MTA nor PyST activate the phosphorylation of AKT. The SV40 small T-antigen, which is similar to PyST in containing a J domain and in binding to the PP2A AC dimer, does not activate the MAP kinase cascade, but does stimulate phosphorylation of AKT in a PP2A-dependent manner. These findings highlight a novel role of PP2A in stimulating the MAP kinase cascade and indicate that the similar polyoma and SV40 small T-antigens influence PP2A to activate discrete cellular signaling pathways involved in growth control.AKT ͉ MAP kinase cascade ͉ polyoma virus T-antigens ͉ SV40 small T-antigen A ctivating oncogenes overcome normal cell regulatory control systems and stimulate growth signaling pathways leading to unregulated cell division. The polyoma virus (Py) early region specifies three proteins, large T-antigen (PyLT), middle T-antigen (PyMT), and small T-antigen (PyST), by differential splicing of mRNA derived from the same genomic DNA sequence (1). The membrane-bound PyMT is a potent activating oncogene, which has no intrinsic enzyme activity but acts as a scaffolding protein and binds and modulates the activities of a number of important cellular signaling proteins (1, 2). Studies with PyMT have provided great insight into a number of critical cellular signaling pathways involved in growth control (3).Membrane-bound PyMT binds and activates the cellular Src tyrosine kinase family resulting in phosphorylation of a number of important PyMT tyrosine residues (1, 2) ( Figs. 1 and 2). Phosphorylation of PyMT tyrosine 315 (Y315) results in the binding of the PI3-kinase regulatory p85 subunit and subsequent activation of PI3-kinase activity, resulting in the phosphorylation of a number of cellular targets, including AKT ( Figs. 1 and 2). Phosphorylation of PyMT tyrosine 250 (Y250) results in the binding of the Shc family of cellular proteins. Bound Shc associates with the adapter molecule Grb2, which binds to the Sos guanine nucleotide exchange factor, resulting in the activation of Ras. Ras activation leads to the activation of the Raf-MAP kinase pathway resulting in the phosphorylation of MEK and ERK (Fig. 1). Phosphorylation of PyMT tyrosine 322 (Y322) results i...

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Natural Biology of Polyomavirus Middle T Antigen

Cited by 48 publications

References 393 publications

The Absence of p53 Promotes Metastasis in a Novel Somatic Mouse Model for Hepatocellular Carcinoma

The Absence of p53 Promotes Metastasis in a Novel Somatic Mouse Model for Hepatocellular Carcinoma

Chromosomal instability at a mutational hotspot in polyoma middle T-antigen affects its ability to activate the ARF-p53 tumor suppressor pathway

Polyoma and SV40 proteins differentially regulate PP2A to activate distinct cellular signaling pathways involved in growth control

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