Abstract

The simian virus 40 (SV40) small-t antigen enhances viral transformation efficiency, presumably through its reported effects on cellular growth induction. The recent finding that small-t binds the cellular enzyme, protein phosphatase 2A (PP2A), reducing its activity, provides an important clue to the action of small-t. In the proposed experiments, we will: (1) use defined point mutants to probe the interaction of small-t and PP2A, with particular emphasis on the relationship between PP2A inhibition and the enhancement of transformation, (2) determine sequences of small-t required for interaction with PP2A, (3) define the structure of small-t and the role of metal binding in maintaining structural integrity and on PP2A inhibition, (4) analyze the phosphorylation state of key proteins within infected cells, notably proteins such as the Na+/H+-antiporter, large-T antigen and others known to play a role in growth promotion, (5) express small-t in Saccharomyces cerevesiae to determine whether this affects yeast cell cycle progression, which is well-defined genetically, and (6) study the effects of small-t on intracellular pH control which may result either by activation of the Na+/H+-antiporter, possibly through phosphorylation, or activation of an alternate H+-extrusion pathway.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA021327-15
Application #
3165524
Study Section
Experimental Virology Study Section (EVR)
Project Start
1977-05-01
Project End
1996-04-30
Budget Start
1992-05-01
Budget End
1993-04-30
Support Year
15
Fiscal Year
1992
Total Cost
Indirect Cost

  Institution

Name
Northwestern University at Chicago
Department
Type
Schools of Dentistry
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611

  Publications

Watanabe, Marika; Phamduong, Ellen; Huang, Chu-Han et al. (2013) Formation of covalently modified folding intermediates of simian virus 40 Vp1 in large T antigen-expressing cells. J Virol 87:5053-64
Fahrbach, Kelly M; Katzman, Rebecca B; Rundell, Kathleen (2008) Role of SV40 ST antigen in the persistent infection of mesothelial cells. Virology 370:255-63
Katzman, Rebecca B; Seeger, Mark; Rundell, Kathleen (2008) SV40 reporter viruses. J Virol Methods 150:7-13
Skoczylas, Christine; Henglein, Berthold; Rundell, Kathleen (2005) PP2A-dependent transactivation of the cyclin A promoter by SV40 ST is mediated by a cell cycle-regulated E2F site. Virology 332:596-601
Skoczylas, Christine; Fahrbach, Kelly M; Rundell, Kathleen (2004) Cellular targets of the SV40 small-t antigen in human cell transformation. Cell Cycle 3:606-10
Shaikh, Sophie; Skoczylas, Christine; Longnecker, Richard et al. (2004) Inability of simian virus 40 to establish productive infection of lymphoblastic cell lines. J Virol 78:4917-20
Boyapati, Anita; Wilson, Marlena; Yu, Jing et al. (2003) SV40 17KT antigen complements dnaj mutations in large T antigen to restore transformation of primary human fibroblasts. Virology 315:148-58
Genevaux, Pierre; Lang, Florence; Schwager, Francoise et al. (2003) Simian virus 40 T antigens and J domains: analysis of Hsp40 cochaperone functions in Escherichia coli. J Virol 77:10706-13
Montano, X; Rundell, K (2001) Role of SV40 small t in cell lysis, transformation, and signaling. Methods Mol Biol 165:229-42
Rundell, K; Parakati, R (2001) The role of the SV40 ST antigen in cell growth promotion and transformation. Semin Cancer Biol 11:5-13

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