Caspase-2 function in cell death and disease

细胞死亡是一种专门的过程，称为细胞凋亡，是从体内删除不需要和有害细胞的一种方式。因此，异常细胞凋亡与包括癌症在内的多种疾病相关。例如，抑制细胞凋亡或增强细胞存活的蛋白质的异常水平可导致癌症，并且通常产生对化疗的抗性。为了理解和治疗由异常凋亡引起的癌症，我们需要在分子水平上知道凋亡是如何调节的。细胞凋亡执行的中心是一组称为半胱天冬酶的酶，它们靶向许多细胞蛋白进行特异性切割。在这个提议中，我们将研究其中一种半胱天冬酶（称为caspase-2）的功能，以便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，caspase-2水平在许多癌细胞中降低。人类半胱天冬酶-2基因定位于白血病中经常受影响-缺失的染色体区域，并且半胱天冬酶-2水平已被提出为某些类型白血病患者的缓解和存活的预测因子。我们将研究癌细胞中caspase-2的缺失是否会使它们对药物的杀伤产生抗性，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.