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

ISSN号：1004-0374
期刊名称：《生命科学》
时间：0
分类：Q257[生物学—细胞生物学] Q255[生物学—细胞生物学]
作者机构：[1]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, [2]University of Chinese Academy of Sciences, Beijing 100049, China, [3]Department of Radiology, Shengjing Hospital of China Medical University, Shenyang 110004, China, [4]Cancer Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430032, China, [5]Institute of Basic Medical Sciences of Chinese Academy of Medical Sciences and School of Basic Medicine of Peking Union Medical College, Beijing 100005, China, [6]College of Life Science, Nankai University, Tianjin 300071, China
相关基金：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.

作者： Xiangxuan Zhao[1,2,3], Yong Liu[1,2], Lei Du[1,2], Leya He[4], Biyun Ni[1,2], Junbo Hu[4], Dahai Zhu[5], Quan Chen[1,2,6]

关键词： TGF-Β, 细胞凋亡, 肝癌细胞, 苏氨酸, 诱导, SMAD蛋白, 转化生长因子, 去磷酸化, apoptosis, TGF-β, FoxO3, casein kinasel-ε, hepatocarcinoma

中文摘要：

转变生长因素 --(TGF-) 在恶意的细胞的各种各样的类型上施加 apoptotic 效果，包括肝癌症细胞。然而， TGF- 由导致 apoptosis 的精确机制仍然保持糟糕已知。在现在的学习，我们显示出那 threonine 32 (Thr32 ) FoxO3 的残余是批评的让 TGF- 在 hepatocarcinoma Hep3B 房间经由 Bim 导致 apoptosis。我们的数据证明 TGF- 在 Thr32 通过特定的 de-phosphorylation 导致了 FoxO3 激活。TGF -- 激活的 FoxO3 与 Smad2/3 合作了调停 Bim 起来规定和 apoptosis。在 Thr32 的 FoxO3 (de ) phosphorylation 被酷蛋白 kinase 调整我 --(CKI-) 。由小分子 D4476 的 CKI 抑制能废除 TGF -- 导致的 FoxO/Smad 激活，反向的 Bim 起来规定，和块顺序的 apoptosis。更重要地， CKI- 和 p32FoxO3 的 deregulated 层次在人的恶意的肝纸巾被发现。一起拿，我们的调查结果建议可能有 FoxO3 的 Thr32 为 TGF 是枢轴的一台 CKI-FoxO/Smad-Bim 在引擎 -- 导致的 apoptosis，为肝癌症治疗使它成为一个潜在的治疗学的目标。

英文摘要：

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.

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