Simian virus 40 (SV40) encodes a powerful oncoprotein, large T antigen, that is capable of inducing tumors in animals and transforming cells in culture. T antigen acts in part by inhibiting the action of two tumor suppressor proteins, members of the retinoblastoma (Rb) family, and p53. Several lines of evidence indicate that T antigen has additional functions that contribute to transformation as well. Most studies of SV40 transformation have made use of cultured cells. In this application we propose to study the effects of T antigen expression on the growth-arrested enterocytes and continuously cycling progenitor cells of the mouse small intestine. Because the cycling cells residing in the crypts and the terminally differentiated cells occupying the villi can be isolated, this system allows a combined genetic and biochemical approach to dissecting T antigen's transforming functions. We have found that the transformation of terminally- differentiated enterocytes is dependent on the transcription factor E2F2. In contrast normal intestinal crypt cell proliferation does not require any of the activating E2Fs. The goals of this application are to: (1) determine if T antigen action on the Rb and p53 pathways sufficient for transformation of crypt epithelial cells;(2) assess the mechanisms allowing cell proliferation to proceed in normal crypts in the absence of E2F1-2-3 and, (3) determine whether the activating E2Fs (E2F1, E2F2, and E2F3a) required to establish repression of E2F-target genes?

Public Health Relevance

This project uses the DNA tumor virus SV40 to probe mechanisms of cellular growth control and tissue homeostasis. Understanding these mechanisms should lead to better therapies for cancer and may suggest approaches for the treatment of certain degenerative diseases.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA098956-09
Application #
8249117
Study Section
Virology - B Study Section (VIRB)
Program Officer
Read-Connole, Elizabeth Lee
Project Start
2002-12-01
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
9
Fiscal Year
2012
Total Cost
$312,819
Indirect Cost
$87,284
Name
University of Pittsburgh
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Cecchini, Matthew J; Thwaites, Michael J; Talluri, Srikanth et al. (2014) A retinoblastoma allele that is mutated at its common E2F interaction site inhibits cell proliferation in gene-targeted mice. Mol Cell Biol 34:2029-45
Forero, Adriana; Giacobbi, Nicholas S; McCormick, Kevin D et al. (2014) Simian virus 40 large T antigen induces IFN-stimulated genes through ATR kinase. J Immunol 192:5933-42
Sáenz Robles, Maria Teresa; Chong, Jean Leon; Koivisto, Christopher et al. (2014) Viral oncogene expression in the stem/progenitor cell compartment of the mouse intestine induces adenomatous polyps. Mol Cancer Res 12:1355-64
Saenz Robles, Maria Teresa; Case, Ashley; Chong, Jean-Leon et al. (2011) The retinoblastoma tumor suppressor regulates a xenobiotic detoxification pathway. PLoS One 6:e26019
Rathi, Abhilasha V; Saenz Robles, M Teresa; Cantalupo, Paul G et al. (2009) Simian virus 40 T-antigen-mediated gene regulation in enterocytes is controlled primarily by the Rb-E2F pathway. J Virol 83:9521-31
Chong, Jean-Leon; Wenzel, Pamela L; Saenz-Robles, M Teresa et al. (2009) E2f1-3 switch from activators in progenitor cells to repressors in differentiating cells. Nature 462:930-4
Cantalupo, Paul G; Saenz-Robles, Maria Teresa; Rathi, Abhilasha V et al. (2009) Cell-type specific regulation of gene expression by simian virus 40 T antigens. Virology 386:183-91
Pipas, James M (2009) SV40: Cell transformation and tumorigenesis. Virology 384:294-303
Saenz Robles, Maria Teresa; Pipas, James M (2009) T antigen transgenic mouse models. Semin Cancer Biol 19:229-35
Saenz-Robles, M Teresa; Markovics, Jennifer A; Chong, Jean-Leon et al. (2007) Intestinal hyperplasia induced by simian virus 40 large tumor antigen requires E2F2. J Virol 81:13191-9

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