Threonine 32 （Thr32） of FoxO3 is critical for TGF-β-induced apoptosis via Bim in hepatocarcinoma cells

作     者：Xiangxuan Zhao Yong Liu Lei Du Leya He Biyun Ni Junbo Hu Dahai Zhu Quan Chen 

作者机构：The Joint Laboratory of Apoptosis and Cancer Biology The State Key Laboratory of Biomembrane and Membrane Biotechnology Institute of Zoology Chinese Academy of Sciences Beijing 100101 China University of Chinese Academy of Sciences Beijing 100049 China Department of Radiology Shengjing Hospital of China Medical University Shenyang 110004 China Cancer Research Center Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan 430032 China Institute of Basic Medical Sciences of Chinese Academy of Medical Sciences and School of Basic Medicine of Peking Union Medical College Beijing 100005 China College of Life Science Nankai University Tianjin 300071 China 

出 版 物：《Protein & Cell》 (蛋白质与细胞（英文版）)

年 卷 期：2015年第6卷第2期

页      面：127-138页

核心收录：

学科分类：0710[理学-生物学] 07[理学] 071009[理学-细胞生物学] 09[农学] 0901[农学-作物学] 090102[农学-作物遗传育种] 

基　　金：This work was supported by grants from the National Basic Research Program (973 Program) (Nos. 2007CB914800 and 2006CB910102), the National Natural Science Foundation of China (Grant Nos. 30630038 and 30400098), a project grant from Chinese Academy of Sciences (KSCX2-YW-R-02) to Q.C. We greatly appreciate the gift of CKI-ε (WT and KD mutant) constructs from Dr. Xiaofan Wang (Department of Pharmacology and Cancer Biol- ogy, Duke University Medical Center, Durham, North Carolina, USA). XZ, YL, DL and HL designed, performed experiments and ana- lyzed data XZ., DH, JH, ZL and QC designed experiments, analyzed data, directed the whole study and wrote the manuscript. All authors read and approved the final manuscripts 

主　　题：apoptosis TGF-β FoxO3 casein kinasel-ε hepatocarcinoma 

摘      要：Transforming growth factor-β （TGF-β） exerts apoptotic effects on various types of malignant ceils, including liver cancer cells. However, the precise mechanisms by which TGF-β induces apoptosis remain poorly known. In the present study, we have showed that threonine 32 （Thr32） residue of FoxO3 is critical for TGF-β to induce apoptosis via Bim in hepatocarcinoma Hep3B cells. Our data demonstrated that TGF-βinduced FoxO3 activation through specific de-phosphorylation at Thr32. TGF-β-activated FoxO3 cooperated with Smad2/ 3 to mediate Bim up-regulation and apoptosis. FoxO3 （de）phosphorylation at Thr32 was regulated by casein kinase I-ε （CKI-E）. CKI inhibition by small molecule D4476 could abrogate TGF-β-induced FoxO/Smad acti- vation, reverse Bim up-regulation, and block the sequential apoptosis. More importantly, the deregulated levels of CKI-ε and p32FoxO3 were found in human malignant liver tissues. Taken together, our findings suggest that there might be a CKI-FoxO/Smad-Bim engine in which Thr32 of FoxO3 is pivotal for TGF-β- induced apoptosis, making it a potential therapeutic target for liver cancer treatment.