Caspase-2 function in cell death and disease

细胞死亡是一种特殊的过程，称为细胞凋亡，是从体内清除不需要的有害细胞的一种方式。因此，细胞凋亡异常与包括癌症在内的多种疾病有关。例如，抑制细胞凋亡或提高细胞存活率的蛋白质水平异常可能导致癌症，并经常产生对化疗的耐药性。为了理解和治疗由异常细胞凋亡引起的癌症，我们需要在分子水平上知道细胞凋亡是如何调节的。凋亡执行的中心是一组被称为caspase的酶，它们针对许多细胞蛋白进行特定的切割。在这个方案中，我们将研究其中一种caspase(称为caspase-2)的功能，以更好地了解其在癌细胞凋亡中的潜在作用。最近的一些报告表明，许多癌细胞中caspase-2的水平都降低了。人类caspase-2基因定位于白血病中常受影响和缺失的染色体区域，caspase-2水平被认为是某些类型白血病患者缓解和生存的预测因子。我们将研究癌细胞中caspase-2的缺失是否会使它们对药物产生抗药性，以及缺乏caspase-2的小鼠是否会增加患癌症的可能性。了解caspase-2的功能及其调控可能为癌症治疗提供新的治疗机会和潜在的靶点。

Cell death by a specialised process known apoptosis is a way of deleting unwanted and harmful cells from the body. As such, aberrant apoptosis is associated with a wide array of diseases including cancer. For example, abnormal levels of proteins that suppress apoptosis or enhance cell survival can result in cancer and often produce resistance to chemotherapy. To understand and treat cancers that result from aberrant apoptosis we need to know at a molecular level how apoptosis is regulated. Central to the apoptosis execution are a group of enzymes called caspases that target many cellular proteins for specific cleavage. In this proposal, we will investigate the function of one of the caspases (called caspase-2), in order to better understand its potential role in the apoptosis of cancer cells. A number of recent reports suggest that caspase-2 levels are reduced in many cancer cells. The human caspase-2 gene localizes to a chromosomal region frequently affected- deleted in leukaemia, and caspase-2 levels have been proposed to be predictors of remission and survival in patients with some types of leukaemia. We will study if loss of caspase-2 in cancer cells makes them resistant to killing by drugs and if mice lacking caspase-2 have an increased potential to develop cancer. Understanding caspase-2 function and its regulation is likely to provide new therapeutic opportunities and potential targets for cancer therapy.