TR3/nur77 in Survival and Death of Cancer Cells

描述(由申请人提供)：TR3，也称为NGFI-B或Nur77，是一种 即刻-早期反应基因和一个孤儿成员 类固醇/甲状腺/维甲酸受体超家族。TR3/Nur77不仅发挥了 癌细胞对有丝分裂和凋亡的反应不同 刺激物。TR3/Nur77是如何调节生存和死亡这一对立活动的？ 很有趣，还不为人所知。最近，我们观察到TR3/Nur77在 核内通过抑制维甲酸的表达诱导细胞增殖 酸受体β(RARbeta)，一种有效的生长抑制因子。另外，我们发现， TR3/Nur77，作为对凋亡诱导剂的反应，从 细胞核到细胞质，在那里它驻留在线粒体中以诱导细胞色素 C释放与细胞凋亡。这些结果导致我们提出TR3/Nur77在 细胞核通过抑制RARbeta的表达来诱导细胞增殖。 而它作用于线粒体，触发细胞色素c的释放和细胞凋亡。 在建议的研究中，我们计划： 1.研究TR3/Nur77的细胞定位是否定义了其 在不同类型的细胞中的生物学功能。 2.研究TR3/Nur77对RARβ基因表达的抑制作用。 3.确定TR3/Nur77的线粒体定位是否以及如何触发 细胞色素c的释放与细胞凋亡。 4.探讨Bcl-2介导TR3/Nur77线粒体的可能性 细胞色素c的物理靶向及其诱导释放 与TR3/Nur77的相互作用。 5.确定Jun氨基末端激酶对TR3/Nur77磷酸化的影响 (JNK)关于其核出口和线粒体靶向。 6.评价TR3/Nur77对小鼠肿瘤生长的促有丝分裂和促凋亡作用 裸鼠。 这些研究的结果将通过以下方式加强我们对机制的理解 哪些TR3/Nur77发挥促有丝分裂和凋亡活性及其在 调节肿瘤的发展，并可能提供有价值的信息来确定 TR3/Nur77作为开发新型分子靶点的可行性研究 一代又一代抗癌药物。

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.