泛素连接酶SCF促进GATA3降解。

The ubiquitin ligase SCF promotes GATA3 degradation.

作者信息

Song Nan, Cao Cheng, Tang Yiman, Bi Liyuan, Jiang Yong, Zhou Yongsheng, Song Xin, Liu Ling, Ge Wenshu

机构信息

Tianjin Key Laboratory of Medical Epigenetics, Department of Biochemistry and Molecular Biology, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.

Department of Prosthodontics, Peking University School and Hospital of Stomatology, Beijing, China.

出版信息

J Cell Physiol. 2018 Mar;233(3):2366-2377. doi: 10.1002/jcp.26108. Epub 2017 Sep 4.

DOI:10.1002/jcp.26108

PMID:28722108

Abstract

GATA3 is a key transcription factor in cell fate determination and its dysregulation has been implicated in various types of malignancies. However, how the abundance and function of GATA3 are regulated remains unclear. Here, we report that GATA3 is physically associated with FBXW7α, and FBXW7α destabilizes GATA3 through assembly of a SKP1-CUL1-F-box E3 ligase complex. Importantly, we showed that FBXW7α promotes GATA3 ubiquitination and degradation in a GSK3 dependent manner. Furthermore, we demonstrated that FBXW7α inhibits breast cancer cells survival through destabilizing GATA3, and the expression level of FBXW7α is negatively correlated with that of GATA3 in breast cancer samples. This study indicated that FBXW7α is a critical negative regulator of GATA3 and revealed a pathway for the maintenance of GATA3 abundance in breast cancer cells.

摘要

GATA3是细胞命运决定中的关键转录因子，其失调与多种类型的恶性肿瘤有关。然而，GATA3的丰度和功能如何被调节仍不清楚。在此，我们报道GATA3与FBXW7α在物理上相关联，并且FBXW7α通过组装SKP1-CUL1-F盒E3连接酶复合物使GATA3不稳定。重要的是，我们表明FBXW7α以GSK3依赖的方式促进GATA3的泛素化和降解。此外，我们证明FBXW7α通过使GATA3不稳定来抑制乳腺癌细胞的存活，并且在乳腺癌样本中FBXW7α的表达水平与GATA3的表达水平呈负相关。这项研究表明FBXW7α是GATA3的关键负调节因子，并揭示了一种维持乳腺癌细胞中GATA3丰度的途径。