Genetic analysis of cell death pathways, drug resistance and oncogenic co-operativity in IL-3 dependent cell lines

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The ultimate fate of most of our cells is to die by committing suicide, because they are no longer required, are no longer functioning, or are potentially harmful. This normal physiological process is termed apoptosis . Inappropriate apoptosis can contribute to cell loss following heart attacks, stroke or neurodegenerative diseases, such as Alzheimer s or Parkinson s disease. Conversely, when cell death fails to occur, abnormal cells can accumulate and lead to cancer. In addition, because drugs that are used to treat cancer may exert their effect by inducing apoptosis, a failure of this suicide response may cause resistance to chemotherapy. The genes of the apoptosis pathway function either to promote or inhibit cell death. We have found that some genes in the apoptosis pathway allow apoptosis to proceed rapidly, but do not decide the fate of the cell. Other genes are required for a cell to commit to die. If these genes are mutated then apoptosis does not occur and a functional cell may survive. The distinction between cells that decide fate and those that do not is crucial because it is only the genes that decide cell fate that can act as cancer genes, and are valid targets for therapy. We use a model in which apoptosis is caused by removal of a growth factor, using cell lines derived from mice that lack particular genes in the cell death pathway. These cells proliferate normally in the presence of growth factor, and allow us to determine the role of the genes when growth factor is withdrawn. Because these cells are sensitive to chemotherapeutic drugs, we can also determine the contribution these genes make to cancer drug sensitivity. Using this system, we have discovered that Puma, a gene known to be required for apoptosis in response to radiation, is also a critical activator of apoptosis following growth factor withdrawal. We will determine the manner in which Puma is regulated by growth factors, as well as identify and characterise other key components.