Regulation of muscle atrophy-related genes by the opposing transcriptional activities of ZEB1/CtBP and FOXO3.
Regulation of muscle atrophy-related genes by the opposing transcriptional activities of ZEB1/CtBP and FOXO3.
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DOI：
10.1093/nar/gky835
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发表时间：
2018-11-16
影响因子：
14.9
通讯作者：
Postigo A
中科院分区：
文献类型：
--
作者：
Ninfali C;Siles L;Darling DS;Postigo A
多种生理和临床条件通过诱导一组包括泛素-蛋白酶体和自噬-溶酶体系统成分的蛋白质(萎缩基因)来触发骨骼肌萎缩。反义基因是由FOXO转录因子诱导的，但其调控机制尚不完全清楚。在这里，我们展示了转录因子ZEB1，众所周知的促进肿瘤进展，通过拮抗FOXO_3介导的萎缩基因的诱导来抑制肌肉萎缩和萎缩基因的表达。与野生型小鼠相比，ZEB1基因缺陷小鼠的后肢制动导致肌肉萎缩加剧，许多萎缩基因的表达增加，包括Atrogin-1/Fbxo32、MuRF1/Trim63、CTSL、4EBP1、Gabarapl1、Psma1和Nrf2。同样，在C2C12肌源性细胞模型中，ZEB1基因敲除既增加了肌管直径的缩小，也增加了对营养缺乏的反应中阿托品的上调。在机制上，ZEB1在体外和体内以阶段依赖的方式直接抑制Fbxo32和Trim63启动子的转录，并与MYOD1相反。ZEB1在未分化成肌细胞和萎缩性肌管中与Fbxo32启动子结合，但在非萎缩性肌管中不结合，在非萎缩性肌管中被MYOD1取代。ZEB1通过CtBP介导的FOXO_3转录活性抑制这两个启动子。这些结果使ZEB1成为治疗导致肌肉质量下降的临床疾病的新靶点。
Multiple physiopathological and clinical conditions trigger skeletal muscle atrophy through the induction of a group of proteins (atrogenes) that includes components of the ubiquitin–proteasome and autophagy-lysosomal systems. Atrogenes are induced by FOXO transcription factors, but their regulation is still not fully understood. Here, we showed that the transcription factor ZEB1, best known for promoting tumor progression, inhibits muscle atrophy and atrogene expression by antagonizing FOXO3-mediated induction of atrogenes. Compared to wild-type counterparts, hindlimb immobilization in Zeb1-deficient mice resulted in enhanced muscle atrophy and higher expression of a number of atrogenes, including Atrogin-1/Fbxo32, MuRF1/Trim63, Ctsl, 4ebp1, Gabarapl1, Psma1 and Nrf2. Likewise, in the C2C12 myogenic cell model, ZEB1 knockdown augmented both myotube diameter reduction and atrogene upregulation in response to nutrient deprivation. Mechanistically, ZEB1 directly represses in vitro and in vivo Fbxo32 and Trim63 promoter transcription in a stage-dependent manner and in a reverse pattern with MYOD1. ZEB1 bound to the Fbxo32 promoter in undifferentiated myoblasts and atrophic myotubes, but not in non-atrophic myotubes, where it is displaced by MYOD1. ZEB1 repressed both promoters through CtBP-mediated inhibition of FOXO3 transcriptional activity. These results set ZEB1 as a new target in therapeutic approaches to clinical conditions causing muscle mass loss.
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影响因子：
4.8
作者：
Sacheck, Jennifer M.;Hyatt, Jon-Philippe K.;Goldberg, Alfred L.
通讯作者：
Goldberg, Alfred L.
影响因子：
16.6
作者：
Milan, Giulia;Romanello, Vanina;Pescatore, Francesca;Armani, Andrea;Paik, Ji-Hye;Frasson, Laura;Seydel, Anke;Zhao, Jinghui;Abraham, Reimar;Goldberg, Alfred L.;Blaauw, Bert;DePinho, Ronald A.;Sandri, Marco
通讯作者：
Sandri, Marco
影响因子：
11.4
作者：
Postigo, AA;Sheppard, AM;Dean, DC
通讯作者：
Dean, DC
影响因子：
4.8
作者：
Lecker, SH;Jagoe, RT;Goldberg, AL
通讯作者：
Goldberg, AL
影响因子：
5.3
作者：
GENETTA, T;RUEZINSKY, D;KADESCH, T
通讯作者：
KADESCH, T