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Post translational modifications (PTM) of C/EBPß and functional implications

C/EBPà 的翻译后修饰 (PTM) 和功能意义

基本信息

批准号：
70796845
负责人：
Professor Dr. Achim Leutz
金额：
--
依托单位：
Forschungsgruppe Zelldifferenzierung und Tumorigenese
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2008
资助国家：
德国
起止时间：
2007-12-31 至 2019-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/70796845?language=en
关键词：
Post translational modifications PTM EBP

项目摘要

A comprehensive and post-translational modification (PTM) dependent interactome of the pioneer transcription factor C/EBPbeta was disclosed using two complementary screening methods (APS and PRISMA) that returned approximately 650 and 1500 proteomic interactions, respectively. Experimentally induced lymphoid - myeloid trans-differen¬tiation revealed that decoration of C/EBPbeta with PTMs determines its reprogramming potential into myeloid sub-lineages and suggested an epigenetic PTM indexing-code on C/EBPbeta. Mixed lineage marker expression is a salient feature of lymphoma entities that express high C/EBPbeta levels, including Hodgkin-, anaplastic large cell-, Mantel cell lymphoma (HL, ALCL, MCL) and multiple myeloma (MM). We consider lineage switching in tumorigenesis in connection with cellular trans-differentiation events and a selective proliferative advantage. To determine the core functions of C/EBPbeta in transformation and lympho-myeloid reprogramming, we will employ state-of-the-art mass spectrometric analysis of the C/EBPbeta PTM index and its interactome in lymphoma cell lines and primary cells, in combination with a CRISPR/Cas9 based functional genomic complementation system of C/EBPbeta mutants in an ALCL cell line. Finally, SUMOylation was identified as a dynamic PTM and bottleneck for additional C/EBPbeta modifications. SUMOylation deficient C/EBPalpha,beta knock in mouse strains have been constructed and will be examined to explore how signaling events are coupled to C/EBPbeta modifications and epigenetic functions.

用两种互补的筛选方法(APS和PRISMA)揭示了先锋转录因子C/EBPbeta的一个依赖于翻译后修饰(PTM)的全面交互作用组，分别返回了约650和1500个蛋白质组相互作用。实验诱导的淋巴-髓系转化实验表明，C/EBPbeta与PTM修饰决定了其重新编程为髓系亚系的潜力，并提出了C/EBPbeta上的表观遗传PTM索引编码。混合谱系标记表达是高C/EBPβ水平淋巴瘤的显著特征，包括霍奇金淋巴瘤、间变性大细胞淋巴瘤、Mantel细胞淋巴瘤(HL、ALCL、MCL)和多发性骨髓瘤(MM)。我们认为，肿瘤发生过程中的谱系转换与细胞转分化事件和选择性增殖优势有关。为了确定C/EBPbeta在转化和淋巴-髓系重编程中的核心功能，我们将使用最先进的质谱分析淋巴瘤细胞系和原代细胞中的C/EBPbeta PTM指数及其相互作用组，并结合ALCL细胞系中基于CRISPR/Cas9的C/EBPbeta突变体的功能性基因组互补系统。最后，SUMO化被认为是一个动态的PTM和额外的C/EBPβ修饰的瓶颈。在小鼠中已经构建了相穆化缺陷C/EBPalpha，β敲击株，并将进行检测，以探索信号事件如何与C/EBPbeta修饰和表观遗传功能耦合。