TR3/nur77 in Survival and Death of Cancer Cells

描述（由申请人提供）：TR 3，也称为NGFI-B或nur 77，是一种 立即早期反应基因和孤儿成员的 类固醇/甲状腺/类维生素A受体超家族。TR 3/nur 77不仅发挥 在癌细胞中对不同的抗肿瘤药物的促有丝分裂和凋亡作用 刺激。TR 3/nur 77如何介导相反的活动，生存和死亡，是 有趣的是，仍然未知。最近，我们观察到TR 3/nur 77在 通过抑制视黄酸的表达来诱导细胞增殖 酸性受体β（RAR β），一种有效的生长抑制剂。此外，我们还发现， TR 3/nur 77，在响应于诱导骨质疏松剂时， 细胞质，在那里它驻留在线粒体中以诱导细胞色素 c释放和凋亡。这些结果使我们提出，TR 3/nur 77作用于 通过抑制RAR β表达诱导细胞增殖。 而它在线粒体中起作用以触发细胞色素C释放和细胞凋亡。 在建议的研究中，我们计划： 1.研究TR 3/nur 77的细胞定位是否定义了其 各种细胞类型的生物学功能。 2.研究TR 3/nur 77对RAR β表达的抑制作用。 3.确定TR 3/nur 77的线粒体定位是否以及如何触发 细胞色素C释放和细胞凋亡。 4.探讨Bcl-2介导TR 3/nur 77线粒体的可能性 靶向和诱导细胞色素c通过其物理释放 与TR 3/nur 77的相互作用。 5.通过Jun N-末端激酶确定TR 3/nur 77磷酸化的影响 (JNK)核输出和线粒体靶向的研究 6.评估TR 3/nur 77对肿瘤生长的促有丝分裂和凋亡作用， 裸鼠 这些研究的结果将增强我们对机制的理解， TR 3/nur 77发挥促有丝分裂和凋亡活性， 调节肿瘤的发展，并可能提供有价值的信息，以确定 使用TR 3/nur 77作为开发新的 一代抗癌药物。

DESCRIPTION (provided by applicant): TR3, also called NGFI-B or nur77, is an immediate-early response gene and an orphan member of the steroid/thyroid/retinoid receptor superfamily. TR3/nur77 exerts not only mitogenic but also apoptotic effects in cancer cells in response to different stimuli. How TR3/nur77 mediates the opposing activities, survival and death, is interesting and remains unknown. Recently, we observed that TR3/nur77 acts in the nucleus to induce cell proliferation by inhibiting expression of retinoic acid receptor beta (RARbeta), a potent growth inhibitor. In addition, we found that TR3/nur77, in response to apoptosis-inducing agents, translocates from the nucleus to the cytoplasm, where it resides in mitochondria to induce cytochrome c release and apoptosis. These results led us to propose that TR3/nur77 acts in the nucleus to induce cell proliferation by inhibiting RARbeta expression. whereas it acts in mitochondria to trigger cytochrome c release and apoptosis. In the proposed studies, we plan to: 1. Investigate whether cellular localization of TR3/nur77 defines its biological functions in various cell types. 2. Study the inhibitory effect of TR3/nur77 on RARbeta expression. 3. Determine whether and how mitochondrial localization of TR3/nur77 triggers cytochrome c release and apoptosis. 4. Explore the possibility that Bcl-2 acts to mediate TR3/nur77 mitochondrial targeting and its induction of cytochrome c release through its physical interaction with TR3/nur77. 5. Determine the effects of TR3/nur77 phosphorylation by Jun N-terminal kinase (JNK) on its nuclear export and mitochondrial targeting. 6. Evaluate mitogenic and apoptotic effects of TR3/nur77 on tumor growth in nude mice. Results from these studies will enhance our understanding of the mechanisms by which TR3/nur77 exerts mitogenic and apoptotic activities and its role in regulating tumor development, and may provide valuable information to determine the feasibility of using TR3/nur77 as a molecular target for developing new generation of anti-cancer drugs.