Regulation of DNA synthesis in mouse embryonic stem cells by transforming growth factor-α: Involvement of the PI3-K/Akt and Notch/Wnt signaling pathways

Abstract

This study examined the mechanisms by which transforming growth factor (TGF)-α regulates proliferation of mouse embryonic stem (ES) cells. TGF-α increased [³H] thymidine and BrdU incorporation in a time- (0–72 h) and dose-dependent (0–10 ng/ml) manner. TGF-α stimulated the phosphorylation of Akt, mammalian target of rapamycin (mTOR), p70S6K1 and p44/42 mitogen-activated protein kinases (MAPKs). TGF-α also increased the protein levels of Notch, Notch intracellular domain, Hes-1 and Wnt1. However, TGF-α-induced DNA synthesis was blocked by inhibition of Akt, mTOR, p44/42 MAPKs and Notch. TGF-α increased the gene expression of c-jun, c-myc and c-fos. Moreover, TGF-α increased cyclin D/CDK 4 and cyclin E/CDK 2 levels, while decreasing p21^cip1/waf1 and p27^kip1, which were blocked by the inhibition of Akt, mTOR and Notch. In conclusion, TGF-α regulated DNA synthesis of mouse ES cells via PI3-K/Akt, p44/42 MAPKs and Notch/Wnt pathways.

• Mouse embryonic stem cell
• TGF-α
• PI3-K/Akt
• p44/42 MAPKs
• Notch