Apoptosis is a programmed form of cell death that is essential for normal development and tissue homeostasis. In malignancy, apoptosis is an important process in tumor suppression; hence, mutations that disable apoptosis can promote tumor progression and resistance to cancer therapy. The adenovirus E1A oncogene rnimics oncogenic changes occurring in spontaneous tumors and is a useful tool for studying apoptosis. E1A is a potent mitogenic oncogene, but also promotes apoptosis as part of a cellular failsafe mechanism that suppresses oncogenic transformation. Using E1A, we have implicated the p53 tumor suppressor gene in apoptosis and demonstrated that inactivation of pS3-dependent apoptosis can promote oncogenic transformation, tumor development, and resistance to cytotoxic agents. More recently, we have used both the E1A the c-myc oncogenes to identify components of p53-dependent and independent apoptotic signaling pathways (e.g. ARF, Rb, Apaf-1, caspases), and begun to assemble these components into a tumor suppressor network. Here, we propose to further define how E1A promotes apoptosis in primary cells, and to use this foundation as a guide to cellular molecules that suppress tumor development or alter tumor-cell sensitivity to cytotoxic agents. Our proposal represents a collaborative and ambitious research plan that is well-grounded in preliminary data. It is multidisciplinary, and combines primary cell genetics, cDNA arrays, and new transgenic technologies to dissect and characterize components of this tumor suppressor network in cultured cells, animal models, and ultimately human tumor cells.
In Aim 1, we identify cellular targets of E1A involved in inducing p53 and promoting apoptosis;
in Aim 2, we study select E1A effectors (e.g. ARF,caspases) that contribute to p53-dependent and independent aspects of apoptotic signaling;
in Aim 3, we dissect the p53 apoptotic program during tumor suppression in a transgenic mouse model; finally,in Aim 4, we study the clinical and biological implications of Apaf-1 inactivation in melanoma. Together, these experiments represent a comprehensive effort to understand fundamental aspects of tumor suppression. These studies will undoubtedly increase our understanding of the natural safeguards that suppress tumor development, and may identify strategies for improving cancer therapy.
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