Investigating common and distinct mechanisms of c-Rel and OTUD4 in lymphoma (P05)

研究 c-Rel 和 OTUD4 在淋巴瘤中的共同和不同机制 (P05)

• 批准号: 405441409
• 金额: --
• 依托单位: Klinik und Poliklinik für Innere Medizin III: Hämatologie und Onkologie
• 依托单位国家: 德国
• 项目类别: Collaborative Research Centres
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/405441409?language=en
• 关键词: Investigating; common; distinct; mechanisms; Rel

Amplification of the NF-κB transcription factor c-REL genomic locus is frequently observed in lymphoma, but the consequences for B cell biology and lymphomagenesis remained enigmatic. We generated the first mouse models for c-Rel gain, which displayed increased germinal centre B cells and autoimmunity. We have also obtained evidence for novel post-transcriptional and post-translational regulation of c-Rel. In particular, the OTUD4 ubiquitin protease is a new vulnerability in lymphoma that mediates c-Rel stabilization and its nuclear localization. Here, we will analyse the molecular regulation of c-Rel and OTUD4 activity in detail, investigate the collaborative oncogenic network of c-Rel and dissect the c-Rel-OTUD4 axis as well as additional OTUD4 targets in lymphoma.

在淋巴瘤中经常观察到NF-κB转录因子c-REL基因组位点的扩增，但对B细胞生物学和淋巴瘤发生的影响仍然是个谜。我们产生了第一个c-Rel增加的小鼠模型，其显示出增加的生发中心B细胞和自身免疫。我们还获得了新的转录后和翻译后调节c-Rel的证据。特别地，OTUD 4泛素蛋白酶是淋巴瘤中介导c-Rel稳定化及其核定位的新的脆弱性。在这里，我们将详细分析c-Rel和OTUD 4活性的分子调控，研究c-Rel的协同致癌网络，并剖析c-Rel-OTUD 4轴以及淋巴瘤中的其他OTUD 4靶点。