Conversion of Bcl-2 by Orphan Nuclear Receptor Nur77

描述（由申请人提供）：Nur 77，也称为TR 3或NGFI-B，是一种立即早期反应基因，是类固醇/甲状腺/维甲酸受体超家族的孤儿成员。Nur 77在细胞中对不同的刺激不仅发挥存活作用，而且还发挥凋亡作用。我们先前证明，Nur 77在响应某些凋亡刺激时可以从细胞核迁移到细胞质，在那里它通过与Bcl-2的相互作用靶向线粒体。Nur 77与Bcl-2的相互作用诱导Bcl-2构象变化，导致Bcl-2从抗凋亡分子转化为促凋亡分子。我们最近对Nur 77- Bcl-2相互作用的研究揭示了Bcl-2天然非结构化环中的一个意想不到的蛋白质-蛋白质相互作用位点，该位点不同于已知负责Bcl-2与其他Bcl-2家族成员相互作用的经典BH 3结合沟。因此，我们假设Bcl-2构象变化是控制细胞存活和死亡的重要机制，并且它是药物开发的有吸引力的靶点。在拟议的研究中，我们计划：目标1。研究Bcl-2环结合位点及其磷酸化调控。目标2.确定生长因子存活信号在调节Bcl-2转换中的作用。目标3：鉴定小分子Bcl-2转化体。目标4。研究Bcl-2转换器的治疗作用。从这些研究中获得的结果将提高我们对Bcl-2转换和调节的分子机制的理解，并可能导致识别新的策略和药物用于癌症治疗。 公共卫生相关性：我们最近发现，Bcl-2可以通过核受体Nur 77从抗凋亡分子转化为促凋亡分子，通过Bcl-2环中新的结合位点介导它们的相互作用。我们建议在这里研究Nur 77与抗凋亡Bcl-2家族成员相互作用的分子机制以及相互作用的功能后果。此外，我们计划探索Bcl-2转换的治疗潜力。我们提出的研究有望为Bcl-2转化提供重要的机制见解，并鉴定新的小分子Bcl-2转化体，这可能广泛适用于治疗人类癌症和其他以Bcl-2水平升高为特征的疾病。

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.