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

我们大多数细胞的最终命运是通过自杀而死亡，因为它们不再需要，不再起作用，或者是潜在的有害物质。这种正常的生理过程被称为细胞凋亡。不适当的细胞凋亡可能导致心脏病发作、中风或神经退行性疾病（如阿尔茨海默病或帕金森病）后的细胞丢失。相反，当细胞死亡没有发生时，异常细胞会积累并导致癌症。此外，因为用于治疗癌症的药物可以通过诱导细胞凋亡来发挥其作用，这种自杀反应的失败可能会导致对化疗的抵抗。细胞凋亡途径的基因起促进或抑制细胞死亡的作用。我们已经发现，凋亡途径中的一些基因允许凋亡快速进行，但不决定细胞的命运。其他基因是细胞死亡所必需的。如果这些基因发生突变，则不会发生细胞凋亡，功能细胞可以存活。决定命运的细胞和不决定命运的细胞之间的区别是至关重要的，因为只有决定细胞命运的基因才能作为癌症基因，并且是治疗的有效靶点。我们使用了一个模型，其中细胞凋亡是由去除生长因子引起的，使用的细胞系来自缺乏细胞死亡途径中特定基因的小鼠。这些细胞在生长因子的存在下正常增殖，并允许我们确定生长因子被撤回时基因的作用。由于这些细胞对化疗药物敏感，我们还可以确定这些基因对癌症药物敏感性的贡献。使用这个系统，我们已经发现，Puma，一个已知的细胞凋亡所需的基因在辐射响应，也是一个关键的细胞凋亡激活剂生长因子撤出。我们将确定Puma受生长因子调节的方式，以及识别和鉴定其他关键成分。

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normally in the presence of growth factor, and allow us to determine the role of the genes when growth factor is withdrawn.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.