Threonine 32 (Thr32) of FoxO3 is critical for TGF-β-induced apoptosis via Bim in hepatocarcinoma cells
Protein & Cell
;
(12): 127-138, 2015.
Article
in English
| WPRIM
| ID: wpr-757611
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.
Full text:
Available
Index:
WPRIM (Western Pacific)
Main subject:
Pathology
/
Threonine
/
Gene Expression Regulation, Neoplastic
/
Transforming Growth Factor beta
/
Proto-Oncogene Proteins
/
Apoptosis
/
Carcinoma, Hepatocellular
/
Cell Line, Tumor
/
Apoptosis Regulatory Proteins
/
Forkhead Transcription Factors
Limits:
Humans
Language:
English
Journal:
Protein & Cell
Year:
2015
Type:
Article
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