SV4O induces tumors in animals and transforms cells in culture by altering the activities of key regulatory circuits that govern cell proliferation and death. Two viral proteins, large T antigen and small t antigen, contribute to tumorigenesis. Small t antigen acts, in part, by inhibiting the pp2A phosphatase. The transforming activity of large T antigen requires its intervention on the Rb and p53 tumor suppressor pathways. Large T antigen directly associates with all three members of the Rb-family and with p53. T antigen mutants that fail to associate with Rb or p53 are defective for some aspect of transformation. We have shown that the amino-terminal 82 amino acids of large and small T antigens is a J domain and that both of these proteins function as DnaJ molecular chaperones. Furthermore, we have shown that the J domain acts in cis with the Rb-binding motif to effect T antigen-mediated release of E2F from Rb. Thus, T antigen does not simply sequester Rb, but rather participates in catalytic disruption of multiprotein complexes containing Rb and E2F. Date from our laboratory, as well as others, also indicates that T antigen does not block p53 function by simple sequestration. During the next period of support we will: (1) explore the mechanism by which the J domain contributes to T antigen action on Rb/E2F complexes. (2) determine how T antigen action on RbIE2F contributes to the transformed phenotype. (3) determine the mechanisms used by T antigen to block p53 function.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA040586-16
Application #
6331486
Study Section
Virology Study Section (VR)
Program Officer
Blair, Donald G
Project Start
1985-07-01
Project End
2006-03-31
Budget Start
2001-04-27
Budget End
2002-03-31
Support Year
16
Fiscal Year
2001
Total Cost
$264,594
Indirect Cost
Name
University of Pittsburgh
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
053785812
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Rathi, Abhilasha V; Cantalupo, Paul G; Sarkar, Saumendra N et al. (2010) Induction of interferon-stimulated genes by Simian virus 40 T antigens. Virology 406:202-11
Cantalupo, Paul G; Sáenz-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
Ahuja, Deepika; Rathi, Abhilasha V; Greer, Amy E et al. (2009) A structure-guided mutational analysis of simian virus 40 large T antigen: identification of surface residues required for viral replication and transformation. J Virol 83:8781-8
Wright, Christine M; Chovatiya, Raj J; Jameson, Nora E et al. (2008) Pyrimidinone-peptoid hybrid molecules with distinct effects on molecular chaperone function and cell proliferation. Bioorg Med Chem 16:3291-301
Zhao, Xiaorong; Madden-Fuentes, Ramiro J; Lou, Becky X et al. (2008) Ataxia telangiectasia-mutated damage-signaling kinase- and proteasome-dependent destruction of Mre11-Rad50-Nbs1 subunits in Simian virus 40-infected primate cells. J Virol 82:5316-28
Saenz-Robles, M T; Toma, D; Cantalupo, P et al. (2007) Repression of intestinal drug metabolizing enzymes by the SV40 large T antigen. Oncogene 26:5124-31
Ahuja, Deepika; Saenz-Robles, M Teresa; Pipas, James M (2005) SV40 large T antigen targets multiple cellular pathways to elicit cellular transformation. Oncogene 24:7729-45
Cantalupo, Paul; Doering, Adrienne; Sullivan, Christopher S et al. (2005) Complete nucleotide sequence of polyomavirus SA12. J Virol 79:13094-104
Markovics, Jennifer A; Carroll, Patrick A; Robles, M Teresa Saenz et al. (2005) Intestinal dysplasia induced by simian virus 40 T antigen is independent of p53. J Virol 79:7492-502

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