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

这个子项目是众多研究子项目之一

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.