AR COBRE: PROTEIN INTERACTIONS IN CARCINOGENESIS AND CANCER TREATMENT

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。 细胞凋亡，或程序性细胞死亡，是一种对多细胞生物体的正常发育和组织稳态至关重要的生化途径。细胞凋亡功能障碍会导致人类癌症和其他疾病的发生。Bcl2蛋白家族在细胞凋亡过程中起着至关重要的作用。Bax是Bcl2家族中控制线粒体介导的细胞死亡途径的两个关键蛋白之一。在正常的健康细胞中，Bax定位于胞浆中，并维持在非活性状态。在细胞凋亡的刺激下，Bax经历了构象变化，并从胞浆迁移到线粒体。Bax通过将其疏水的C末端插入线粒体外膜，破坏线粒体膜电位，诱导线粒体释放促凋亡蛋白，进而触发细胞凋亡。是什么使Bax在健康细胞的胞浆中保持其不活跃的构象，以及什么因素在凋亡刺激下触发了Bax的构象变化，目前尚不清楚。我们的初步数据显示，在健康细胞的胞浆中，除了大部分单体Bax外，还有一小部分Bax与高相对分子质量的蛋白质复合体有关。我们假设，在健康或凋亡细胞中与Bax相关的蛋白质是Bax在细胞凋亡中激活的关键。

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. Apoptosis, or programmed cell death, is a biochemical pathway critical to normal development and tissue homeostasis in multi-cellular organisms. Dysfunction of apoptosis results in development of human cancer and other diseases. The Bcl-2 family of proteins constitutes a crucial checkpoint in the apoptosis pathway. Bax is one of the two key proteins (Bax and Bak) of the Bcl-2 family that control the mitochondrion-mediated cell death pathway. In normal healthy cells, Bax locates in the cytosol and is maintained in the inactive state. Upon apoptotic stimulation, Bax undergoes conformational changes, and migrates from the cytosol to mitochondria. By insertion of its hydrophobic C-terminal end to the mitochondrial outer membrane, Bax disrupts mitochondrial membrane potential, and induces the release of pro-apoptotic proteins from mitochondria, which in turn triggers apoptosis. What maintains Bax in its inactive conformation in the cytosol of healthy cells, and what factors trigger the conformational changes of Bax upon apoptotic stimulation remain unclear. Our preliminary data showed that in addition to the majority of monomeric Bax, a small portion of Bax was associated with high molecular weight protein complexes in the cytosol of healthy cells. We hypothesize that the proteins that associate with Bax in healthy or apoptotic cells hold the key to Bax activation in apoptosis.