Conversion of Bcl-2 by Orphan Nuclear Receptor Nur77

描述（由申请人提供）：Nur77，也称为TR3或NGFI-B，是一种立即早期反应基因，是类固醇/甲状腺/类视黄醇受体超家族的孤儿成员。在不同的刺激下，Nur77不仅在细胞中发挥存活作用，而且在细胞中发挥凋亡作用。我们之前已经证明，Nur77对某些凋亡刺激的反应可以从细胞核迁移到细胞质，通过与Bcl-2的相互作用靶向线粒体。Nur77与Bcl-2相互作用诱导Bcl-2构象改变，导致Bcl-2从抗凋亡分子转化为促凋亡分子。我们最近对Nur77- Bcl-2相互作用的研究发现，在Bcl-2的天然非结构环中存在一个意想不到的蛋白质-蛋白质相互作用位点，这与已知负责Bcl-2与其他Bcl-2家族成员相互作用的经典bh3结合槽不同。因此，我们假设Bcl-2构象变化是控制细胞生存和死亡的重要机制，是药物开发的一个有吸引力的靶点。在拟进行的研究中，我们计划：目的1。表征Bcl-2环结合位点及其磷酸化调控。目标2。目的探讨生长因子生存信号在Bcl-2转化调控中的作用。目标3。鉴定小分子Bcl-2转化器。目标4。目的：研究Bcl-2转化器的治疗效果。这些研究结果将增强我们对Bcl-2转化和调控的分子机制的理解，并可能导致癌症治疗的新策略和药物的确定。

DESCRIPTION (provided by applicant): Nur77, also called TR3 or NGFI-B, is an immediate-early response gene and an orphan member of the steroid/thyroid/retinoid receptor superfamily. Nur77 exerts not only survival but also apoptotic effects in cells in response to different stimuli. We previously demonstrated that Nur77 in response to certain apoptotic stimuli could migrate from the nucleus to the cytoplasm, where it targets mitochondria through its interaction with Bcl-2. Nur77 interaction with Bcl-2 induces a Bcl-2 conformational change, resulting in conversion of Bcl-2 from an anti-apoptotic to a pro-apoptotic molecule. Our recent investigation of Nur77- Bcl-2 interaction revealed an unexpected protein-protein interaction site in the natively unstructured loop of Bcl-2, which differs from the classical BH3-binding groove known to be responsible for interaction of Bcl-2 with other Bcl-2 family members. Thus, we hypothesize that Bcl-2 conformational change is an important mechanism governing the survival and death of cells and it is an attractive target for drug development. In the proposed studies, we plan: Aim 1. To characterize the Bcl-2 loop binding site and its regulation by phosphorylation. Aim 2. To determine the role of growth factor survival signaling in the regulation of Bcl-2 conversion. Aim 3. To identify small molecule Bcl-2 converters. Aim 4. To study the therapeutic effects of Bcl-2 converters. Results obtained from these studies will enhance our understanding of the molecular mechanism of Bcl-2 conversion and regulation and may lead to identification of new strategies and agents for cancer therapy. PUBLIC HEALTH RELEVANCE: We recently discovered that Bcl-2 can be converted from an anti-apoptotic to a pro-apoptotic molecule by nuclear receptor Nur77 through their interaction mediated by a new binding site in the loop of Bcl-2. We propose here to study the molecular mechanism by which Nur77 interacts with anti-apoptotic Bcl-2 family members and the functional consequences of the interaction. In addition, we plan to explore the therapeutic potential of Bcl-2 conversion. Our proposed studies are anticipated to provide important mechanistic insight into Bcl-2 conversion and to identify new small molecule Bcl-2 converters, which could find broad applicability to treating human cancers and other diseases characterized by elevated levels of Bcl-2.