UVRAG AUTOPHAGIC TUMOR SUPPRESSOR PROTEIN

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，即细胞质成分的降解，是一种进化上保守的动态平衡过程，涉及环境适应、寿命决定和肿瘤发展。肿瘤抑制因子Beclin1是PI3KC3(PI3KC3)脂蛋白激酶复合体的一部分，可诱导自噬。然而，Beclin1-PI3KC3复合体的自噬活性却被Bcl2抑制。在这里，我们报告了一种新的螺旋线圈UVRAG候选肿瘤抑制因子，作为Beclin1-PI3KC3复合体的正调控因子。UVRAG与Beclin1-Bcl2-PI3KC3多蛋白复合体相关，UVRAG和Beclin1相互依赖地诱导自噬，UVRAG在人类结肠癌中高频率地单等位突变。UVRAG介导的Beclin1-PI3KC3复合体的激活不仅促进自噬，而且抑制人结肠癌细胞的增殖和致瘤性。

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, the degradation of cytoplasmic components, is an evolutionarily conserved homeostatic process involved in environmental adaptation, lifespan determination, and tumor development. The tumor suppressor, Beclin1, is part of the PI3 kinase class III (PI3KC3) lipid kinase complex that induces autophagy. The autophagic activity of Beclin1-PI3KC3 complex, however, is suppressed by Bcl-2. Here, we report the identification of a novel coiled-coil UVRAG tumor suppressor candidate as a positive regulator of Beclin1-PI3KC3 complex. UVRAG, which is monoallelically mutated at high frequency in human colon cancers, associates with the Beclin1-Bcl-2-PI3KC3 multiprotein complex, where UVRAG and Beclin1 interdependently induce autophagy. UVRAG-mediated activation of Beclin1-PI3KC3 complex not only promotes autophagy but also suppresses the proliferation and tumorigenicity of human colon cancer cells.