Non-apoptotic functions of caspases

描述(由申请人提供)：细胞迁移和侵袭是肿瘤转移的关键方面，目前还不完全清楚。最近，我们发现，凋亡调节因子caspase-8可以促进肿瘤细胞的迁移和侵袭，还可以调节细胞骨架的其他方面的调节，包括钙蛋白激活、Rac激活、片状脂血症的产生和细胞黏附。我们建议阐明caspase-8控制这些过程的机制。在第一个特定的目标中，我们将确定caspase-8是如何控制钙蛋白酶的激活的，特别是caspase-8对黏附复合体对钙蛋白酶的磷酸化和激活的影响。在特定的目标2中，我们将检验caspase-8通过刺激Calain介导的鸟核苷酸交换因子(GEF)对RAC的切割和/或通过调节PI3-Kinase的P85亚基来增强RAC激活的假说。特殊目的3利用人类乳腺癌的基因定义和良好特征的小鼠模型来测试caspase-8在肿瘤转移中的作用。Caspase-8在大多数人类肿瘤类型中都有表达。它可能协调细胞凋亡和细胞运动信号的相反过程，这两个过程分别由成熟或未加工的酶执行。了解caspase-8这一新功能对肿瘤发生和人类癌症治疗的影响是很重要的。

DESCRIPTION (provided by applicant): Cell migration and invasion are critical aspects of tumor metastasis that are incompletely understood. Recently, we have found that the apoptosis regulator, caspase-8, enhances cell migration and invasion of tumor cells, as well as modulating other aspects of cytoskeletal regulation, including calpain activation, Rac activation, generation of lamellipodia, and cell adhesion. We propose to elucidate the mechanisms whereby caspase-8 controls these processes. In the first specific aim, we will determine how caspase-8 controls calpain activation, particularly the effects of caspase-8 on the phosphorylation and activation of calpains by adhesion complexes. In specific aim 2, we will examine the hypotheses that caspase-8 enhances Rac activation by stimulating the calpain-mediated cleavage of guanine nucleotide exchange factors (GEFs) for Rac and/or by regulating the p85 subunit of PI3- Kinase. Specific aim 3 utilizes a genetically defined and well-characterized mouse model for human breast cancer to test the effects of caspase-8 on tumor metastasis. Caspase-8 expression is retained in most human tumor types. It may coordinate the opposing processes of apoptosis vs. cell motility signaling, which are carried out by the mature or unprocessed forms of the enzyme, respectively. It is important to understand the ramifications of this novel function of caspase-8 for oncogenesis and the treatment of human cancer.