期刊
CELL RESEARCH
卷 22, 期 1, 页码 237-247出版社
SPRINGERNATURE
DOI: 10.1038/cr.2011.127
关键词
Wnt pathway; Axin/beta-catenin complex; small molecule; mesenchymal stem cell
类别
资金
- SK Biopharmaceuticals Co., Ltd
- Kookmin University in Korea
- National Research Foundation of Korea (NRF)
- Ministry of Education, Science and Technology [2009-0072221]
The Wnt/beta-catenin pathway plays important roles in the differentiation of multiple cell types, including mesenchymal stem cells. Using a cell-based chemical screening assay with a synthetic chemical library of 270 000 compounds, we identified the compound SKL2001 as a novel agonist of the Wnt/beta-catenin pathway and uncovered its molecular mechanism of action. SKL2001 upregulated beta-catenin responsive transcription by increasing the intracellular beta-catenin protein level and inhibited the phosphorylation of beta-catenin at residues Ser33/37/Thr41 and Ser45, which would mark it for proteasomal degradation, without affecting CK1 and GSK-3 beta enzyme activities. Biochemical analysis revealed that SKL2001 disrupted the Axin/beta-catenin interaction, which is a critical step for CK1- and GSK-3 beta-mediated phosphorylation of beta-catenin at Ser33/37/Thr41 and Ser45. The treatment of mesenchymal stem cells with SKL2001 promoted osteoblastogenesis and suppressed adipocyte differentiation, both of which were accompanied by the activation of Wnt/beta-catenin pathway. Our findings provide a new strategy to regulate mesenchymal stem cell differentiation by modulation of the Wnt/beta-catenin pathway.
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