BIF-1 INTERACTS WITH BECLIN 1 AND REGULATES AUTOPHAGY AND TUMORIGENESIS

BIF-1 与 BECLIN 1 相互作用并调节自噬和肿瘤发生

• 批准号: 7562108
• 负责人: Yoshimitsu Takahashi
• 金额: $ 3.16万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7562108
• 关键词: 1-Phosphatidylinositol 3-Kinase; Apoptosis; Autophagocytosis; Caspase; Cell Death; Cells; Cellular Stress; Class; Computer Retrieval of Information on Scientific Projects Database; Cytosol; Development; Eating; Family; Funding; Grant; Institution; Knock-out; Lipids; Mediator of activation protein; Mus; Nutrient; Phosphoinositide-3-Kinase, Catalytic, Gamma Polypeptide; Phosphotransferases; Process; Research; Research Personnel; Resources; Role; Source; Starvation; United States National Institutes of Health; Vesicle; Withdrawal; caspase-3; member; nutrition; response; tumor; tumorigenesis

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Autophagy is an evolutionarily conserved "self-eating" process that is activated in response to environmental and cellular stresses. However, the role of this mechanism in cell demise and tumor development remains a topic of hot debate. Here, we demonstrate that loss of Bif-1, a member of the endophilin B family, suppresses autophagy-dependent cell death and promotes tumorigenesis in mice. In response to nutrient starvation, Bif-1 acts as a positive mediator of the PI3-kinase class III (PI3KC3) lipid kinase that interacts with Beclin 1 through UVRAG and translocates from the cytosol to LC3-positive vesicles. Inactivation of autophagy suppresses caspase-independent cell death but promotes caspase-3 activation following nutrition withdrawal. In spite of the enhanced caspase activity, there is much less cell death in total when autophagy is inhibited, indicating that autophagy induces caspase-independent cell death while inhibiting caspase-dependent apoptosis. Moreover, knockout of Bif-1 significantly enhances the development of spontaneous tumors in mice.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 自噬是一种进化上保守的“自食”过程，在环境和细胞应激时被激活。然而，这种机制在细胞死亡和肿瘤发展中的作用仍然是一个热门话题。在这里，我们证明了Bif-1的损失，一个成员的内啡肽B家族，抑制自噬依赖性细胞死亡，促进小鼠肿瘤的发生。响应于营养饥饿，Bif-1作为PI 3-激酶III类（PI 3 KC 3）脂质激酶的正介体，其通过UVRAG与Beclin 1相互作用并从胞质溶胶易位到LC 3阳性囊泡。自噬失活抑制caspase-3非依赖性细胞死亡，但促进caspase-3激活后营养撤退。尽管增强的半胱天冬酶活性，但当自噬被抑制时，总的细胞死亡少得多，表明自噬诱导半胱天冬酶非依赖性细胞死亡，同时抑制半胱天冬酶依赖性细胞凋亡。此外，敲除Bif-1显著增强小鼠中自发性肿瘤的发展。