Polyomavirus causes a broad spectrum of tumors. Because it requires cellular S phase to replicate, polyoma has evolved diverse mechanisms by which transforming gene products (T antigens) promote cell cycle progression. Since these mechanisms target normal cell components of growth control, information gained here is generally relevant to the problem of neoplasia. This work involves aspects of each of the 3 transforming gene products. An N-terminal J domain common all 3 T antigens connects them to chaperone systems. J function is clearly different for different T antigens. LT regulates Rb tumor suppressors by both J dependent and J independent mechanisms; experiments will determine the range of Rb family functions that LT affects by each mechanism. Sequences in Rb required for J inactivation will be determined. Experiments on p130, an Rb family member associated with cell cycle withdrawal will determine the basis for, and consequences of LT induced phosphorylation. We will probe the structure and function of J domains in large T(LT) and small T(ST) to differentiate sequences required for large T(LT) regulation of tumor suppressors of the retinoblastoma susceptibility (Rb) gene family from those connected to small T(ST) regulation of protein phosphatase 2A(PP2A). The contributions of the J domain structure to virus replication will be dissected. Cellular J domains will be tested to determine whether they regulate normal cellular gene expression. Novel functions in LT that regulate cell growth and gene expression will be mapped, and their cellular targets determined. Large T phosphorylation sites will be determined and tested to determine whether they regulate interactions with the tumor suppressors. Middle T (MT) is critical for tumor induction. Novel sites of tyrosine phosphorylation will be mapped and their function tested by mutation. The cellular proteins interacting with those sites will be determined. Since the ability of MT to cause tumors and to promote cell survival is strongly connected to interaction with phosphatidylinositol 3-kinase (PI3K), the connection between MT function and PDK1, a newly discovered initial target of inositol phospholipids, will be examined.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA034722-19
Application #
6375664
Study Section
Experimental Virology Study Section (EVR)
Program Officer
Read-Connole, Elizabeth Lee
Project Start
1983-04-03
Project End
2004-01-31
Budget Start
2001-03-31
Budget End
2002-03-30
Support Year
19
Fiscal Year
2001
Total Cost
$417,229
Indirect Cost
Name
Tufts University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02111
Denis, Deborah; Rouleau, Cecile; Schaffhausen, Brian S (2017) A Transformation-Defective Polyomavirus Middle T Antigen with a Novel Defect in PI3 Kinase Signaling. J Virol 91:
Rouleau, Cecile; Pores Fernando, Arun T; Hwang, Justin H et al. (2016) Transformation by Polyomavirus Middle T Antigen Involves a Unique Bimodal Interaction with the Hippo Effector YAP. J Virol 90:7032-7045
Pores Fernando, A T; Andrabi, S; Cizmecioglu, O et al. (2015) Polyoma small T antigen triggers cell death via mitotic catastrophe. Oncogene 34:2483-92
Utermark, Tamara; Schmit, Fabienne; Lee, Sang Hyun et al. (2014) The phosphatidylinositol 3-kinase (PI3K) isoform dependence of tumor formation is determined by the genetic mode of PI3K pathway activation rather than by tissue type. J Virol 88:10673-9
Hwang, Justin H; Pores Fernando, Arun T; Faure, Nathalie et al. (2014) Polyomavirus small T antigen interacts with yes-associated protein to regulate cell survival and differentiation. J Virol 88:12055-64
Harrison, Celia; Jiang, Tao; Banerjee, Pubali et al. (2013) Polyomavirus large T antigen binds symmetrical repeats at the viral origin in an asymmetrical manner. J Virol 87:13751-9
Hwang, Justin H; Jiang, Tao; Kulkarni, Shreya et al. (2013) Protein phosphatase 2A isoforms utilizing A? scaffolds regulate differentiation through control of Akt protein. J Biol Chem 288:32064-73
Banerjee, Pubali; DeJesus, Rowena; Gjoerup, Ole et al. (2013) Viral interference with DNA repair by targeting of the single-stranded DNA binding protein RPA. PLoS Pathog 9:e1003725
Miao, B; Skidan, I; Yang, J et al. (2012) Inhibition of cell migration by PITENINs: the role of ARF6. Oncogene 31:4317-32
Lee, Sang Hyun; Jia, Shidong; Zhu, Yanni et al. (2011) Transgenic expression of polyomavirus middle T antigen in the mouse prostate gives rise to carcinoma. J Virol 85:5581-92

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