摘要

The transcription factor c-Maf is extensively involved in the pathophysiology of multiple myeloma (MM), a fatal malignancy of plasma cells. In the present study, affinity chromatography and mass spectrometry were used to identify c-Maf ubiquitination-associated proteins, from which the E3 ligase HERC4 was found to interact with c-Maf and catalyzed its polyubiquitination and subsequent proteasome-mediated degradation. HERC4 mediated polyubiquitination at K85 and K297 in c-Maf, and this polyubiquitination could be prevented by the isopeptidase USP5. Further analysis on the NCI-60 cell line collection revealed that RPMI 8226, a MM-derived cell line, expressed the lowest level of HERC4. Primary bone marrow analysis revealed HERC4 expression was high in normal bone marrow, but was steadily decreased during myelomagenesis. These findings suggested HERC4 played an important role in MM progression. Moreover, ectopic HERC4 expression decreased MM proliferation in vitro, and delayed xenograft tumor growth in vivo. Therefore, modulation of c-Maf ubiquitination by targeting HERC4 may represent a new therapeutic modality for MM. 

译文

转录因子 c-Maf 广泛参与多发性骨髓瘤 (MM) 的病理生理过程,MM 是一种致命的浆细胞恶性肿瘤。在本研究中,亲和色谱和质谱用于鉴定 c-Maf 泛素化相关蛋白, 从中发现 E3 连接酶 HERC4 与 c-Maf 相互作用,并催化其多聚泛素化和随后蛋白酶体介导的降解。HERC4 介导了 c-Maf 中 K85 和 K297 的多聚泛素化,这种多聚泛素化可以被异肽酶 usp5 阻止。对 NCI-60 细胞系收集的进一步分析显示,MM 来源的细胞系 RPMI 8226 表达的 herc4 水平最低。初级骨髓分析显示 HERC4 在正常骨髓中高表达,但在骨髓再生过程中稳步下降。这些发现表明 HERC4 在 MM 进展中发挥了重要作用。此外,HERC4 的异位表达降低了体外 MM 的增殖,并延缓了体内异种移植瘤的生长。因此,通过靶向 HERC4 来调节 c-Maf 泛素化可能代表了 MM 的一种新的治疗方式。

Nude Mice

肿瘤 突变小鼠 实验动物
概述  :  

裸鼠,即是先天性胸腺缺陷的突变小鼠,是由于第Ⅶ连锁群(Linkage group)内裸体位点的等位基因发生纯合而形成的突变小鼠新品种。裸鼠是随着近代医学发展,特别是肿瘤学和免疫学研究的需要,在近十几年中发展起来的动物模型。在肿瘤学、免疫学、药品与生物制品的安全性评价及有效药品的筛选等实验方面有着特殊的价值。裸鼠(纯合子nu/nu突变鼠)主要表现为无毛(但可看到一种细毛组织学证明有被毛滤泡)以及缺乏正常胸腺。 杂合子小鼠(nn/+)各方面表现都正常。小鼠中有若干突变基因,它可产生一种

Nude   英 /njuːd/   美 /nuːd/

释    义   adj. 裸的,裸体的;无装饰的;与生俱有的;n. 裸体;裸体画

例    句   The relevance of using nude mouse models for evaluating drug delivery to human tumors has recently been questioned by numerous researchers. 使用裸鼠模型评估药物给药对人类肿瘤的相关性最近受到许多研究人员的质疑。

 

Mice   英 /maɪs/   美 /maɪs/

释    义   n. 老鼠(mouse的复数)

例    句   He has gathered evidence from mice to support this idea, but whether it is the case in people has yet to be tested. 他已经从老鼠实验中收集了支持这一观点的证据,但它对人是否也起作用还有待进一步测试。

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