Non-apoptotic functions of caspases

Caspases的非凋亡功能

• 批准号: 7379834
• 负责人: Steven Miles Frisch
• 金额: $ 27.36万
• 依托单位: WEST VIRGINIA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-12-10 至 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7379834
• 关键词: 1-Phosphatidylinositol 3-Kinase; Adhesions; Apoptosis; Apoptosis Regulator; Apoptotic; Breast Cancer Model; Calpain; Caspase; Cell Adhesion; Clinical Trials; Complex; ERBB2 gene; Enzymes; Future; Generations; Guanine Nucleotide Exchange Factors; Human; Knock-out; Knockout Mice; Light; MAP3K1 gene; Malignant Neoplasms; Mammary gland; Mediating; Molecular Profiling; Mus; Mutation; Neoplasm Metastasis; Oncogenes; Pathway interactions; Phosphoinositide-3-Kinase, Catalytic, Gamma Polypeptide; Phosphorylation; Process; Regulation; Risk; Role; Signal Transduction; Site; Testing; Therapeutic; Transgenic Organisms; Tumor Cell Invasion; Variant; base; cancer therapy; caspase-8; cell motility; chemotherapy; inhibitor/antagonist; malignant breast neoplasm; migration; mouse model; neoplastic cell; novel; pre-clinical; tumor; tumor progression; tumorigenesis

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.

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，这些方面尚未完全理解。最近，我们发现凋亡调节剂CASPASE-8增强了细胞迁移和侵袭肿瘤细胞，并调节细胞骨架调节的其他方面，包括钙蛋白酶激活，RAC活化，lamellipodia的产生，层状脂蛋白和细胞粘附。我们建议阐明caspase-8控制这些过程的机制。在第一个特定目的中，我们将确定caspase-8如何控制钙蛋白酶的激活，尤其是caspase-8对通过粘附复合物对钙蛋白酶磷酸化和激活的影响。在特定目标2中，我们将通过刺激RAC和/或调节PI3-激酶的P85亚基来刺激calpain介导的鸟嘌呤核苷酸交换因子（GEF）的裂解来增强RAC激活的假设。特定的目标3利用了人类乳腺癌的遗传定义和特征良好的小鼠模型来测试caspase-8对肿瘤转移的影响。 caspase-8表达保留在大多数人类肿瘤类型中。它可以协调凋亡与细胞运动信号的相对过程，这些过程分别由酶的成熟或未加工形式进行。重要的是要了解caspase-8在肿瘤发生和治疗人类癌症治疗方面的新​​功能的后果。