The Regulation and Role of Puma and p53 in IL-3 withdrawal induced cell death

我们大多数细胞的最终命运是自杀，因为它们不再被需要，不再发挥作用，或者有潜在的危害。这种正常的生理过程被称为细胞凋亡。当细胞死亡失败时，异常细胞会积聚并导致癌症。许多细胞类型的生存都需要来自生长因子的信号。当这些信号丢失时，细胞就会激活它们的细胞死亡途径。癌细胞的一个特征是它们在细胞死亡基因中含有突变，并且它们对生长因子的依赖减少或丧失。凋亡通路的基因或促进或抑制细胞死亡。凋亡途径中的一些基因允许细胞凋亡快速进行，但不决定细胞的命运。细胞死亡需要其他基因，如果它们发生突变，那么一个能够增殖的功能细胞就会存活下来。这是一个至关重要的区别，因为只有决定细胞命运的基因才能作为癌症基因，并且是有效的治疗目标。我们已经确定了一个特殊的基因，Puma，作为细胞存活的重要调节因子。没有这种基因，细胞在没有生长因子的情况下存活的时间更长，更重要的是，当生长因子恢复时，细胞可以增殖。了解这种基因的功能和调控方式将有助于我们了解导致癌症的基因突变，并可能确定癌症治疗的有效靶点。在我们的模型中，我们使用了生长因子依赖细胞系，这些细胞系来源于缺乏细胞死亡途径中特定基因的小鼠，包括Puma。这些细胞在生长因子存在的情况下增殖，使我们能够确定当生长因子被撤回时基因的作用。利用这个系统，我们将确定Puma是如何诱导细胞死亡的，还需要哪些基因来调节这一过程，以及Puma功能的丧失是如何导致癌症发展的。

It is the ultimate fate of most of our cells 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 . When cell death fails to occur, abnormal cells can accumulate and lead to cancer. Signalling from growth-factors is required for many cell types to survive. When these signals are lost, the cells activate their cell death pathways. It is a hallmark of cancer cells that they harbour mutations in cell death genes and their dependence on growth factors for survival is diminished or lost. The genes of the apoptosis pathway function either to promote or inhibit cell death. 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, and if they are mutated then a functional cell, that is capable of proliferating, survives. This is a crucial distinction because it is only the genes that decide cell fate that can act as cancer genes, and are valid targets for therapy. We have identified one particular gene, Puma, as an important regulator of cell survival. Without this gene, cells survive longer without growth-factor and, importantly, can proliferate when growth factor is restored. Understanding how this gene functions and is regulated will contribute to our understanding of the gene mutations that lead to cancer and may identify valid targets for cancer therapy. In our model we use growth factor dependent cell lines derived from mice lacking particular genes in the cell death pathway, including Puma. These cells proliferate in the presence of growth factor, and allow us to determine the role of the genes when growth factor is withdrawn. Using this system, we will determine how Puma is able to induce cell death, what other genes are required to regulate this process and how loss of Puma function may contribute to cancer development.