Acute infection by the small DNA tumor virus, SV40, can drive quiescent mammalian cells into the cell cycle. At least part of this work is performed by SV40 LT, one of the two viral oncoproteins. The rest is performed by the other oncoprotein, SV40 ST. The role of ST in this process depends upon its ability to interfere with the function of the protein phosphatase, PP2A, the product of a known human.tumor suppressing gene. Unexpectedly, at least part of the mechanism underlying SV40 ST perturbation of quiescence control is directed at events that occur in G2 (or G2/M). The process targeted by ST during G2 is PP2A- dependent and must be intact for cells to quiesce following mitogen deprivation initiated during the next G1 phase. Also involved is the p130/E2F4/DREAM complex, the integrity of which is PP2A dependent, This complex has been shown to operate in the maintenance of quiescence. Whether G2-centered PP2A function and/or PP2A function operating at another time(s) during the cell cycle communicates with this complex to license quiescence is unclear. The thrust of the proposed research is aimed at understanding 1) how, in molecular terms, the G2 quiescence control process operates, 2) whether its perturbation contributes to SV40 STdependent neoplastic transformation and tumorigenesis and 3), if this is the case, how its perturbation elicits these effects.
The work proposed in this project focuses on one of the cardinal properties of normal cells-their ability to escape the cell cycle. Most cancer cells cannot escape the cell cycle, possibly adding to their ability to proliferate in an uncontrolled manner. By understanding why normal cells escape and cancer cells cannot, we hope to unearth a better appreciation for why tumors expand at various rates. Detailed molecular knowledge of this type will, ideally, create new cancer therapeutic opportunities.
|Cizmecioglu, Onur; Ni, Jing; Xie, Shaozhen et al. (2016) Rac1-mediated membrane raft localization of PI3K/p110Î² is required for its activation by GPCRs or PTEN loss. Elife 5:|
|Galligan, Jeffrey T; Martinez-NoÃ«l, Gustavo; Arndt, Verena et al. (2015) Proteomic analysis and identification of cellular interactors of the giant ubiquitin ligase HERC2. J Proteome Res 14:953-66|
|Howley, Peter M; Pfister, Herbert J (2015) Beta genus papillomaviruses and skin cancer. Virology 479-480:290-6|
|Hettmer, Simone; Schinzel, Anna C; Tchessalova, Daria et al. (2015) Functional genomic screening reveals asparagine dependence as a metabolic vulnerability in sarcoma. Elife 4:|
|Berrios, Christian; Jung, Joonil; Primi, Blake et al. (2015) Malawi polyomavirus is a prevalent human virus that interacts with known tumor suppressors. J Virol 89:857-62|
|Spurgeon, Megan E; Cheng, Jingwei; Bronson, Roderick T et al. (2015) Tumorigenic activity of merkel cell polyomavirus T antigens expressed in the stratified epithelium of mice. Cancer Res 75:1068-79|
|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|
|White, Elizabeth A; Kramer, Rebecca E; Hwang, Justin H et al. (2015) Papillomavirus E7 oncoproteins share functions with polyomavirus small T antigens. J Virol 89:2857-65|
|Luo, Leo Y; Kim, Eejung; Cheung, Hiu Wing et al. (2015) The Tyrosine Kinase Adaptor Protein FRS2 Is Oncogenic and Amplified in High-Grade Serous Ovarian Cancer. Mol Cancer Res 13:502-9|
|White, Elizabeth A; Walther, Johanna; Javanbakht, Hassan et al. (2014) Genus beta human papillomavirus E6 proteins vary in their effects on the transactivation of p53 target genes. J Virol 88:8201-12|
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