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

Puma 和 p53 在 IL-3 戒断诱导的细胞死亡中的调节和作用

• 批准号: nhmrc : 436936
• 负责人: A/Pr Christine Hawkins
• 金额: $ 35.19万
• 依托单位: Murdoch Childrens Research Institute
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2007
• 资助国家: 澳大利亚
• 起止时间: 2007-01-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/regulation-role-puma-cell-death/96922
• 关键词: Regulation; Role; Puma; p53; IL

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proliferate in the presence of growth factor, and allow us to determine the role of the genes when growth factor is withdrawn.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

我们大多数细胞的最终命运是自杀，因为它们不再需要，不再起作用，或者有潜在的危害。这种正常的生理过程被称为细胞凋亡。当细胞死亡未能发生时，异常细胞会积聚并导致癌症。来自生长因子的信号传导是许多细胞类型存活所必需的。当这些信号丢失时，细胞激活它们的细胞死亡途径。癌细胞的一个标志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性降低或丧失。细胞凋亡途径的基因起促进或抑制细胞死亡的作用。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，如果它们发生突变，那么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，并且是有效的治疗靶点。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更长时间，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节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，我们使用生长因子依赖性细胞系，这些细胞系来自细胞死亡途径中缺乏特定基因的小鼠，包括Puma。这些细胞在生长因子存在的情况下增殖，并允许我们确定当生长因子被撤回时基因的作用。使用这个系统，我们将确定Puma如何能够诱导细胞死亡，需要哪些其他基因来调节这一过程，以及Puma功能的丧失如何有助于癌症的发展。