Abstract
Glycogen synthase kinase-3β (GSK3β) is a major negative modulator of cardiac hypertrophy. Here we report that GSK3β physically and functionally interacts with Smad3. The interaction between GSK3β and Smad3 may participate in the negative regulation of transforming growth factor β1 (TGF-β1) and Angiotensin II-induced transcription and apoptosis. GSK3β interacted directly with Smad3 to sequester it outside the nucleus and prevent its nuclear translocation. This resulted in the suppression of Smad3-mediated transcriptional activity and gene expression. GSK3β counteracted the pro-apoptotic effect of Smad3 and attenuated Angiotensin II-induced apoptosis in cardiac myocytes. Furthermore, stimulation of these cells with TGF-β1 and Angiotensin II led to the endogenous Smad3 disassociating from GSK3β and inactivating GSK3β by phosphorylation of its Ser9. These results uncovered a novel mechanism for the GSK3β negative regulation of TGF-β1/Smad3 and Angiotensin II/Smad3-mediated transcription and apoptosis by the identification of a crosstalk between GSK3β and Smad3 signal pathway.
Original language | English (US) |
---|---|
Pages (from-to) | 17-23 |
Number of pages | 7 |
Journal | European Journal of Pharmacology |
Volume | 644 |
Issue number | 1-3 |
DOIs | |
State | Published - Oct 2010 |
Funding
This work was supported by grants from the National Major Basic Research Program of China (973: # 2006CB503808 ) and the National Natural Science Foundation of China ( 30472025 ). Dr. Zhuowei Hu is also supported by Cheung-Kong Scholars Programme of the Ministry of Education and by a Senior Oversea Chinese Scholar Fund from the Ministry of Personnel of PRC.
Keywords
- Angiotensin II
- Glycogen synthase kinase-3β
- Protein interaction
- Smad3
- Transforming growth factor β1
ASJC Scopus subject areas
- Pharmacology