Threonine 32 (Thr32) of FoxO3 is critical for TGF-β-induced apoptosis via Bim in hepatocarcinoma cells.
10.1007/s13238-014-0121-5
- Author:
Xiangxuan ZHAO
1
;
Yong LIU
;
Lei DU
;
Leya HE
;
Biyun NI
;
Junbo HU
;
Dahai ZHU
;
Quan CHEN
Author Information
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, zhaoxiangxuan@gmail.com.
- Publication Type:Journal Article
- MeSH:
Apoptosis;
genetics;
Apoptosis Regulatory Proteins;
biosynthesis;
Bcl-2-Like Protein 11;
Carcinoma, Hepatocellular;
genetics;
pathology;
Cell Line, Tumor;
Forkhead Box Protein O3;
Forkhead Transcription Factors;
genetics;
Gene Expression Regulation, Neoplastic;
Humans;
Liver Neoplasms;
genetics;
pathology;
Membrane Proteins;
biosynthesis;
Proto-Oncogene Proteins;
biosynthesis;
Threonine;
genetics;
Transforming Growth Factor beta;
genetics
- From:
Protein & Cell
2015;6(2):127-138
- CountryChina
- Language:English
-
Abstract:
Transforming growth factor-β (TGF-β) exerts apoptotic effects on various types of malignant cells, 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-β induced 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-ε). CKI inhibition by small molecule D4476 could abrogate TGF-β-induced FoxO/Smad activation, 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.
