15-Deoxy-D12, 14-PGE, J2 as a ligand of RXRalpha

15-脱氧-D12、14-PGE、J2 作为 RXRalpha 的配体

• 批准号: 7923023
• 负责人: XIAO-KUN ZHANG
• 金额: $ 12万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7923023
• 关键词: 9-deoxy-delta-9-prostaglandin D2; Affinity; Anti-Inflammatory Agents; Anti-inflammatory; Apoptosis; Apoptotic; Binding; Cell Nucleus; Coupled; Cytoplasm; DNA Binding; Dimerization; Docking; Figs - dietary; Goals; Heterodimerization; Homodimerization; In Vitro; Inflammation; Interdisciplinary Study; Lead; Ligand Binding Domain; Ligands; Malignant Neoplasms; Mediating; Mitochondria; Molecular; Molecular Target; Mutagenesis; NR4A1 gene; Nuclear Export; Nuclear Orphan Receptor; Nude Mice; Pathway interactions; Peroxisome Proliferator-Activated Receptors; Phosphorylation; Play; Preventive; Process; Prostaglandin D2; Prostaglandins D; Proteins; RNA Interference; RXR; Role; Signal Pathway; Small Interfering RNA; Structure; Therapeutic; Transactivation; Transfection; Xenograft Model; analog; base; cancer cell; computer studies; cytochrome c; design; flexibility; in vivo; lipid metabolism; novel; orphan nuclear receptor TR3; receptor; scaffold

DESCRIPTION (provided by applicant): 15-Deoxy-?12, 14-prostaglandin J2 (15d-PGJ2), a natural metabolite of prostaglandin D2 (PGD2), has potent pro-apoptotic activity in cancer cells. Although 15d-PGJ2 is the highest affinity natural ligand for peroxisome proliferator-activated receptor ??(PPAR?), the actual molecular target of 15d-PGJ2 for inducing apoptosis remains to be identified and characterized. Recently, we discovered a novel apoptotic pathway in cancer cells, in which orphan nuclear receptor TR3 translocates from the nucleus to the mitochondrion to induce cytochrome c (cyt c) release and apoptosis. In our preliminary studies, we observed that TR3 must heterodimerize with retinoid X receptor ? (RXR?) to translocate from the nucleus to the cytoplasm, where TR3 binds mitochondrial Bcl-2 to induce cyt c release and apoptosis. In addition, we discovered that 15d- PGJ2 binds RXR? and induces RXR? translocation from the nucleus to the cytoplasm, resulting in cotranslocation of TR3. These exciting findings lead us to propose that 15d-PGJ2 is a natural RXR? ligand, which acts by inducing RXR? cytoplasmic activity, and that 15d-PGJ2 promotes cancer cell apoptosis by inducing RXR?/TR3 cytoplasmic localization and mitochondrial targeting. The major objectives of this multidisciplinary research application are to study how binding of 15d-PGJ2 to RXR? regulates RXR? nuclear export and TR3-dependent apoptosis and on the basis of these findings develop efficient synthetic analogs that selectively modulate RXR? cytoplasmic action (rexporters). Four Aims are proposed to accomplish our goals: 1. To determine the role of RXRs in mediating the apoptotic effects of 15d-PGJ2 in vitro and in vivo using RXR? stable transfection and RNAi approaches. 2. To investigate the molecular mechanisms by which 15d-PGJ2 binding modulates receptor dimerization and nuclear export of RXR? and its heterodimers, as well as how TR3 phosphorylation by Akt regulates RXR??TR3 dimerization and nuclear export. 3. To examine the effect of 15d-PGJ2 binding on the interaction of the RXR?/TR3 heterodimer and Bcl-2 and its impact on mitochondrial activities. 4. To design and synthesize 15d-PGJ2 analogs with enhanced RXR selectivity and activity using computational approaches coupled with the results of bioevaluation. Results obtained from our studies will establish 15d-PGJ2 as a natural RXR? ligand regulating a novel RXR signaling pathway, enhance our understanding of the molecular mechanism by which 15d-PGJ2 induces apoptosis, and lead to the identification of more effective synthetic rexporters with cancer preventive value.

性状（申请人提供）：15-脱氧-？12，14-前列腺素J2（15d-PGJ2）是前列腺素D2（PGD2）的天然代谢产物，在癌细胞中具有强的促凋亡活性。虽然15d-PGJ 2是过氧化物酶体增殖物激活受体的最高亲和力的天然配体，但它的生物学活性和生物学活性与过氧化物酶体增殖物激活受体的生物学活性密切相关。(PPAR?), 15d-PGJ 2诱导细胞凋亡的实际分子靶点仍有待鉴定和表征。最近，我们发现了一种新的癌细胞凋亡途径，其中孤儿核受体TR3从细胞核易位到细胞核，诱导细胞色素c（cyt c）释放和凋亡。在我们的初步研究中，我们观察到TR3必须异源二聚体与维甲酸X受体？(RXR?)从细胞核转位到细胞质，在细胞质中TR3结合线粒体Bcl-2以诱导细胞色素c释放和凋亡。另外，我们发现15d-PGJ 2与RXR结合。并诱发RXR从细胞核到细胞质的易位，导致TR3的共易位。这些令人兴奋的发现使我们提出，15d-PGJ2是一种天然的RXR？配体，其通过诱导RXR起作用？15d-PGJ2通过诱导RXR？/ TR3细胞质定位和线粒体靶向。这个多学科研究应用的主要目标是研究如何结合15 d-PGJ2的RXR？调节RXR？核出口和TR3依赖性细胞凋亡，并在这些研究结果的基础上开发有效的合成类似物，选择性地调节RXR？细胞质作用（rexporters）。我们提出了四个目标来实现我们的目标：1。为了确定RXR在介导15 d-PGJ 2在体外和体内使用RXR的凋亡效应的作用？稳定转染和RNAi方法。2.研究15d-PGJ2结合调节RXR受体二聚化和核输出的分子机制。和它的异源二聚体，以及如何TR3磷酸化Akt调节RXR？TR3二聚化和核输出。3.为了检测15d-PGJ2结合对RXR？/ TR3异源二聚体和Bcl-2及其对线粒体活性的影响4.设计并合成具有增强的RXR选择性和活性的15d-PGJ2类似物，使用计算方法结合生物评价结果。从我们的研究中获得的结果将建立15d-PGJ2作为一个自然的RXR？配体调节一种新的RXR信号通路，增强了我们对15d-PGJ2诱导细胞凋亡的分子机制的理解，并导致鉴定具有癌症预防价值的更有效的合成受体。

项目成果

A structure-based approach to retinoid X receptor-alpha inhibition.

一种基于结构的类维生素A X 受体-α 抑制方法。

• DOI: 10.1074/jbc.m600318200
• 发表时间: 2006
• 期刊: The Journal of biological chemistry
• 作者: Stebbins,JohnL;Jung,Dawoon;Leone,Marilisa;Zhang,Xiao-kun;Pellecchia,Maurizio
• 通讯作者: Pellecchia,Maurizio