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

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 自噬是一种进化上保守的“自噬”过程，是在应对环境和细胞压力时被激活的。然而，这一机制在细胞死亡和肿瘤发展中的作用仍然是一个热门的争论话题。在这里，我们证明了Bif-1的缺失，内嗜素B家族的成员，抑制自噬依赖的细胞死亡，并促进小鼠的肿瘤发生。在营养饥饿的反应中，Bif-1作为PI3-KC3类(PI3KC3)脂蛋白激酶的阳性介体，通过UVRAG与Beclin 1相互作用，并从胞浆转移到Lc3阳性的小泡。自噬的失活抑制了caspase非依赖性的细胞死亡，但促进了营养停用后caspase-3的激活。尽管caspase活性增强，但当自噬被抑制时，细胞死亡总数要少得多，这表明自噬诱导caspase依赖的细胞死亡，同时抑制caspase依赖的凋亡。此外，Bif-1基因的敲除显著增强了小鼠自发肿瘤的发展。

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.