Research Papers:
Atypical ubiquitin E3 ligase complex Skp1PamFbxo45 controls the core epithelialtomesenchymal transitioninducing transcription factors
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Ming Xu1,2, Changhong Zhu2, Xian Zhao2, Cheng Chen2, Hailong Zhang2, Haihua Yuan1, Rong Deng2, Jinzhuo Dou2, Yanli Wang2, Jian Huang2, Qin Chen2, Bin Jiang1 and Jianxiu Yu2,3
1 Institute of Oncology & Department of Oncology, Shanghai 9th People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
2 Department of Biochemistry and Molecular Cell Biology & Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, China
3 State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Correspondence:
Jianxiu Yu, email:
Keywords: Epithelial-mesenchymal transition (EMT), EMT-Inducing Transcription Factors (EMT-TFs), Fbxo45; miR-27a*, ubiquitin degradation
Received: August 05, 2014 Accepted: November 24, 2014 Published: November 25, 2014
Abstract
Epithelial-mesenchymal transition (EMT) plays a critical role in the development of tumor metastases by enhancing migration/invasion. One of the hallmarks of EMT is loss of E-cadherin and gain of N-cadherin expression, which are regulated by the core EMT-inducing transcription factors (EMT-TFs), such as Zeb1/2, Snai1/2 and Twist1. Here, we find that EMT-TFs can be dynamically degraded by an atypical ubiquitin E3 ligase complex Skp1-Pam-Fbxo45 (SPFFbxo45) through the ubiquitin proteasome system (UPS). The key step is recognition of EMT-TFs by Fbxo45 through its SPRY domain for Zeb2, or F-box domain for the other three EMT-TFs Snai1, Snai2 and Twist1, respectively. The K48-linkaged ubiquitination capability on Zeb2 relies on its functional SBD domain. In addition, miR-27a* can directly down-regulate the expression of Fbxo45, preventing degradation of EMT-TFs and thus ensuring EMT phenotype. We suggest that Fbxo45 is a key node of the miR-27a*/Fbxo45/EMT-TFs signaling axis.