) In vitro assays for oncogenic transformation based on rodent cells represent a powerful research tools for investigating radiation carcinogenesis. First, they are highly quantitative; this is true for both C3H, 10T1/2 cells and fresh explants of mouse embryo cells. Second, the influence of specific genes on radiation induced transformation can be studied by using embryo cells. Second, the influence of specific genes on radiation induced transformation can be studied by using embryo cells from knock-out mice. Transformation assays based on human cells are not as quantitative, but are more relevant for seeking genes involved in the oncogenic process. Five questions will be addressed, all of which relate directly to the primary overall goal of this program project, namely an understanding of the mechanisms of alpha-particle induced oncogenesis. (1) Can transformation be induced in cells in which the cytoplasm has been traversed by one or more alpha-particles, but none have penetrated the nucleus? (2) Is there a """"""""bystander effect"""""""" for transformation- i.e. can transformation can induced in cells which are not directly hit, but are in contact and the communication with cells suffering trans-nuclear or trans- cytoplasmic alpha-particles transversals? What are the conditions for the bystander effect to be manifest? (3) Does the transformation incidence resulting from a pair of alpha-particles through the cell nucleus depend on the spatial and temporal separation of the particles? (4) Does the incidence of transformation induced by alpha-particles in mouse embryo cells depend on the status of the ATM gene? (5) Are specific genes consistently unregulated or down-regulated in human cells transformed by alpha-particles.
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