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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Special Emphasis Panel (ZCA1-GRB-S)
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Dana-Farber Cancer Institute
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