scholarly journals Intestinal Dysplasia Induced by Simian Virus 40 T Antigen Is Independent of p53

2005 ◽  
Vol 79 (12) ◽  
pp. 7492-7502 ◽  
Author(s):  
Jennifer A. Markovics ◽  
Patrick A. Carroll ◽  
M. Teresa Sáenz Robles ◽  
Hannah Pope ◽  
Craig M. Coopersmith ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Kinase Inhibitor ◽  
Simian Virus 40 ◽  
Antigen Expression ◽  
Simian Virus ◽  
T Antigen ◽  
Cyclin Dependent Kinase ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Tumor Suppressor Proteins ◽  
Intestinal Hyperplasia

ABSTRACT Transgenic mice expressing simian virus 40 large T antigen in enterocytes develop intestinal hyperplasia that progresses to dysplasia with age. Hyperplasia is dependent on T antigen binding to the retinoblastoma (pRb) family of tumor suppressor proteins. Mice expressing a truncated T antigen that inactivates the pRb-family, but is defective for binding p53, exhibit hyperplasia but do not progress to dysplasia. We hypothesized that the inhibition of the pRb family leads to entry of enterocytes into the cell cycle, resulting in hyperplasia, while inactivation of p53 is required for progression to dysplasia. Therefore, we examined T antigen/p53 complexes from the intestines of transgenic mice. We found that T antigen did not induce p53 stabilization, and we could not detect T antigen/p53 complexes in villus enterocytes. In contrast, T antigen expression led to a large increase in the levels of the cyclin-dependent kinase inhibitor p21. Furthermore, mice in which pRb was inactivated by a truncated T antigen in a p53 null background exhibited intestinal hyperplasia but no progression to dysplasia. These data indicate that loss of p53 function does not play a role in T antigen-induced dysplasia in the intestine. Rather, some unknown function of T antigen is essential for progression beyond hyperplasia.

scholarly journals Enterocyte Proliferation and Intestinal Hyperplasia Induced by Simian Virus 40 T Antigen Require a Functional J Domain

2007 ◽  
Vol 81 (17) ◽  
pp. 9481-9489 ◽  
Author(s):  
Abhilasha V. Rathi ◽  
M. Teresa Sáenz Robles ◽  
James M. Pipas
Keyword(s):  
Transgenic Mice ◽  
Family Members ◽  
Simian Virus 40 ◽  
Simian Virus ◽  
T Antigen ◽  
Wild Type ◽  
Morphological Examination ◽  
Enterocyte Proliferation ◽  
J Domain ◽  
Intestinal Hyperplasia

ABSTRACT Transgenic mice expressing the simian virus 40 large T antigen (TAg) in enterocytes develop intestinal hyperplasia that progresses to dysplasia with age. This induction requires TAg action on the retinoblastoma (Rb) family of tumor suppressors and is independent of the p53 pathway. In cell culture systems, the inactivation of Rb proteins requires both a J domain in TAg that interacts with hsc70 and an LXCXE motif that directs association with Rb proteins. Together these elements are sufficient to release E2Fs from their association with Rb family members. We have generated transgenic mice that express a J domain mutant (D44N) in villus enterocytes. In contrast to wild-type TAg, the D44N mutant is unable to induce enterocyte proliferation. Histological and morphological examination revealed that mice expressing the J domain mutant have normal intestines without loss of growth control. Unlike mice expressing wild-type TAg, mice expressing D44N do not reduce the protein levels of p130 and are also unable to dissociate p130-E2F DNA binding complexes. Furthermore, mice expressing D44N in a null p130 background are still unable to develop hyperplasia. These studies demonstrate that the ectopic proliferation of enterocytes by TAg requires a functional J domain and suggest that the J domain is necessary to inactivate all three pRb family members.

scholarly journals Renal cyst formation and multifocal neoplasia in transgenic mice carrying the simian virus 40 early region.

1991 ◽  
Vol 2 (1) ◽  
pp. 84-97
Author(s):  
K A Kelley ◽  
N Agarwal ◽  
S Reeders ◽  
K Herrup
Keyword(s):  
Transgenic Mice ◽  
Renal Cyst ◽  
Simian Virus 40 ◽  
Antigen Expression ◽  
Simian Virus ◽  
T Antigen ◽  
Tumor Formation ◽  
Large T Antigen ◽  
Early Region ◽  
The Brain

Simian virus 40 early region transgenic mice develop characteristic pathological abnormalities of the brain, kidney, and thymus, due to expression of large-T antigen. Earlier studies have indicated that the most consistent effect of large-T antigen expression is the formation of choroid plexus papillomas in the brain and that thymic hyperplasia and various kidney abnormalities are less frequently observed. The renal lesions reportedly consist of numerous glomerular abnormalities and tubular proliferation. Surprisingly, an analysis of 21 simian virus 40 early region transgenic mice, which were produced for this study, revealed a much higher incidence of polycystic kidney disease as well as earlier development of T-antigen-induced abnormalities. In marked contrast to earlier observations, there is an apparent reduction in the glomerular number in the affected kidneys, whereas the remaining glomeruli appear normal. The most striking feature of the T-antigen-induced renal abnormalities was extensive hyperplasia of tubular epithelial cells which was most marked in the distal tubules; all tubule segments are involved in the most severely affected animals. In most cases, cysts lined with hyperplastic epithelium were observed and papillary structures protruding from the cyst lining were evident. Multiple areas of focal neoplasia were apparent, and, in the most severely affected animals, there were areas in which tumor had replaced normal renal parenchyma. These results strongly suggest that T-antigen-induced renal cyst and tumor formation are part of the same pathological process which is initially manifested as tubular epithelial hyperplasia.

scholarly journals The retinoblastoma protein-binding region of simian virus 40 large T antigen alters cell cycle regulation in lenses of transgenic mice.

1994 ◽  
Vol 14 (10) ◽  
pp. 6743-6754 ◽  
Author(s):  
L Fromm ◽  
W Shawlot ◽  
K Gunning ◽  
J S Butel ◽  
P A Overbeek
Keyword(s):  
Cell Cycle ◽  
Transgenic Mice ◽  
Retinoblastoma Protein ◽  
Simian Virus 40 ◽  
Cell Types ◽  
Simian Virus ◽  
T Antigen ◽  
Lens Fiber ◽  
Large T Antigen ◽  
Fiber Cells

Regulation of the cell cycle is a critical aspect of cellular proliferation, differentiation, and transformation. In many cell types, the differentiation process is accompanied by a loss of proliferative capability, so that terminally differentiated cells become postmitotic and no longer progress through the cell cycle. In the experiments described here, the ocular lens has been used as a system to examine the role of the retinoblastoma protein (pRb) family in regulation of the cell cycle during differentiation. The ocular lens is an ideal system for such studies, since it is composed of just two cell types: epithelial cells, which are capable of proliferation, and fiber cells, which are postmitotic. In order to inactivate pRb in viable mice, genes encoding either a truncated version of simian virus 40 large T antigen or the E7 protein of human papillomavirus were expressed in a lens-specific fashion in transgenic mice. Lens fiber cells in the transgenic mice were found to incorporate bromodeoxyuridine, implying inappropriate entry into the cell cycle. Surprisingly, the lens fiber cells did not proliferate as tumor cells but instead underwent programmed cell death, resulting in lens ablation and microphthalmia. Analogous lens alterations did not occur in mice expressing a modified version of the truncated T antigen that was mutated in the binding domain for the pRb family. These experimental results indicate that the retinoblastoma protein family plays a crucial role in blocking cell cycle progression and maintaining terminal differentiation in lens fiber cells. Apoptotic cell death ensues when fiber cells are induced to remain in or reenter the cell cycle.

Uniform cell-autonomous tumorigenesis of the choroid plexus by papovavirus large T antigens

1991 ◽  
Vol 11 (12) ◽  
pp. 5968-5976
Author(s):  
J D Chen ◽  
T Van Dyke
Keyword(s):  
Transgenic Mice ◽  
Choroid Plexus ◽  
Simian Virus 40 ◽  
Regulatory Elements ◽  
Simian Virus ◽  
T Antigen ◽  
Rapid Expansion ◽  
Morphological Transformation ◽  
Large Tumor ◽  
Lymphotropic Papovavirus

The simian virus 40 (SV40) large tumor antigen (T antigen) under its natural regulatory elements induces choroid plexus papillomas in transgenic mice. Because these tumors develop focally after several months, it has been suggested that secondary cellular alterations are required to induce a tumor in this tissue. In contrast to SV40, the related lymphotropic papovavirus early region induces rapid nonfocal choroid plexus neoplasia in transgenic mice. Here, using hybrid gene constructs, we showed that T antigen from either virus in in fact sufficient to induce these tumors. Their abilities to induce proliferative abnormalities in other tissues, such as kidney and thymus, were also indistinguishable. Differences in the rate of choroid plexus tumorigenesis reflected differences in the control regions of the two viruses, rather than differences in T antigen per se. Under SV40 regulation, expression was limited to a fraction of the choroid plexus cells prior to the formation of focal tumors. When SV40 T antigen was placed under lymphotropic papovavirus control, in contrast, expression was generally uniform in the choroid plexus and rapid expansion of the tissue ensued. We found a direct relationship between T-antigen expression, morphological transformation, and proliferation of the choroid plexus epithelial cells. Analysis of mosaic transgenic mice indicated further that T antigen exerts its mitogenic effect cell autonomously. These studies form the foundation for elucidating the role of various T-antigen subactivities in tumorigenesis.

Antibody response to human papovavirus JC (JCV) and simian virus 40 (SV40) T antigens in SV40 T antigen-transgenic mice

Virology ◽  
1992 ◽  
Vol 190 (1) ◽  
pp. 459-464 ◽  
Author(s):  
Satvir S. Tevethia ◽  
Melanie Epler ◽  
Ingo Georgoff ◽  
Angie Teresky ◽  
Marty Marlow ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Antibody Response ◽  
Simian Virus 40 ◽  
Simian Virus ◽  
T Antigen ◽  
Sv40 T Antigen ◽  
T Antigens ◽  
Human Papovavirus

scholarly journals Downregulation of Protein Disulfide Isomerase Inhibits Infection by the Mouse Polyomavirus

2006 ◽  
Vol 80 (21) ◽  
pp. 10868-10870 ◽  
Author(s):  
Joanna Gilbert ◽  
Wu Ou ◽  
Jonathan Silver ◽  
Thomas Benjamin
Keyword(s):  
Protein Disulfide Isomerase ◽  
Current Knowledge ◽  
Simian Virus 40 ◽  
Antigen Expression ◽  
Simian Virus ◽  
T Antigen ◽  
Disulfide Isomerase ◽  
Cellular Markers ◽  
Interfering Rna ◽  
Protein Disulfide

ABSTRACT Early stages of infection by the mouse polyomavirus have been studied using HeLa cells stably expressing small interfering RNA to protein disulfide isomerase (PDI). Infectibility measured by nuclear T antigen expression was reduced commensurately with the degree of PDI downregulation. Infectibility was restored by transfection with a plasmid expressing PDI but not with a control expressing catalytically inactive enzyme. Deconvolution microscopy using fluorescently labeled virus and cellular markers showed that virus reaches the endoplasmic reticulum (ER) normally in cells with reduced PDI but subsequently fails to exit the ER. Simian virus 40 infection was not inhibited in PDI-downregulated cells. The results are discussed in terms of structural differences between the two viruses and current knowledge of virus disassembly in the ER.

Lectins are sensitive tools for defining the differentiation programs of mouse gut epithelial cell lineages

1994 ◽  
Vol 266 (6) ◽  
pp. G987-G1003 ◽  
Author(s):  
P. Falk ◽  
K. A. Roth ◽  
J. I. Gordon
Keyword(s):  
Epithelial Cell ◽  
Transgenic Mice ◽  
Intestinal Epithelial Cell ◽  
Cell Lineage ◽  
Simian Virus 40 ◽  
Simian Virus ◽  
T Antigen ◽  
Intestinal Epithelial ◽  
Cell Lineages ◽  
Carbohydrate Specificities

We have used histochemical methods to survey the cellular patterns of binding of a panel of 45 lectins with well-defined carbohydrate specificities to sections prepared from various regions of the gastric-to-colonic axis of fetal, neonatal, and adult FVB/N mouse gut. The results suggest that lectins can be used as remarkably sensitive tools to describe the differentiation programs of gastric and intestinal epithelial cell lineages as a function of their position along the cephalocaudal axis of the gut and as a function of developmental stage. Studies of intestinal isografts and transgenic mice that express Simian virus-40 T antigen in enterocytes suggest that many of these cell lineage-specific and spatial patterns of glycoconjugate production can be established and maintained in the absence of exposure to luminal contents and in the presence of specific proliferative abnormalities. This lectin panel should be useful for operationally defining subpopulations of the principal gut epithelial cell lineages in normal strains of mice, for describing variations in gut epithelial cell differentiation programs in mutant and transgenic mice, and for recovering specific epithelial cell lineages or subpopulations.

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