The goal of this project is to gain insight into alterations of cell cycle control mechanisms in neoplastically transformed mammalian cells. A requisite step in the process of carcinogenesis is the loss of normal control of cellular proliferation. This can result, at least in part, from gain-of-function mutations (such as activations of oncogenes), loss-of-function mutations (such as inactivations of normal tumor suppressor gene functions), and both heritable and non-heritable alterations in the normal pattern of gene expression and function. We are studying alterations in growth control signal transduction pathways in genetically altered mammalian cells in culture as compared with their normal counterparts. These studies include investigations of cell cycle related parameters in mouse fibroblasts that constitutively over express specific oncogene products, in human fibroblasts from individuals with heritable genetic alterations predisposing them to various cancers, and in human and mouse cells with one or both wild type alleles of the p53 tumor suppressor gene altered. Specifically, we are investigating cell cycle related parameters, such as the level of expression and phosphorylation status of the cdc2-family of kinases, cyclin proteins, tubulin proteins, reorganization of interphase microtubules to mitotic spindles, and phosphorylation events associated with the activation of microtubule organizing centers (MTOCs) and maturation promoting factor (MPF) activity, in synchronized, clonal populations of NIH3T3 cells or NIH3T3 cells over expressing v-mos, H-ras(val12), and tpr-met. In these studies, we are investigating not only altered cell cycle control due to abnormal gene expression but also cell cycle control in response to environmental stress, such as conditions of nutrient deprivation or exposure to radiation, in these cells. Similar studies are underway that utilize human cells from individuals with heritable cancer syndromes which follow specific gene products, such as p34(cdc2), cyclin proteins, and p53, in these genetically abnormal cells as compared to their normal counterparts as they progress through their division cycle following exposure to ionizing radiation and other environmental insults.
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