ANG II-stimulated DNA synthesis is mediated by ANG II receptor-dependent Ca2+/PKC as well as EGF receptor-dependent PI3K/Akt/mTOR/p70S6K1 signal pathways in mouse embryonic stem cells
✍ Scribed by Ho Jae Han; Ji Yeon Han; Jung Sun Heo; Sang Hun Lee; Min Young Lee; Yun Hee Kim
- Publisher
- John Wiley and Sons
- Year
- 2007
- Tongue
- English
- Weight
- 530 KB
- Volume
- 211
- Category
- Article
- ISSN
- 0021-9541
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✦ Synopsis
Abstract
Effect of angiotensin II (ANG II) on mouse embryonic stem (ES) cell proliferation was examined. ANG II increased [^3^H] thymidine incorporation in a time‐ (>4 h) and dose‐ (>10^−9^ M) dependent manner. The ANG II‐induced increase in [^3^H] thymidine incorporation was blocked by inhibition of ANG II type 1 (AT~1~) receptor but not by ANG II type 2 (AT~2~) receptor, and AT~1~ receptor was expressed. ANG II increased inositol phosphates formation and [Ca^2+^]~i~, and translocated PKC α, δ, and ζ to the membrane fraction. Consequently, the inhibition of PLC/PKC suppressed ANG II‐induced increase in [^3^H] thymidine incorporation. The inhibition of EGF receptor kinase or tyrosine kinase prevented ANG II‐induced increase in [^3^H] thymidine incorporation. ANG II phosphorylated EGF receptor and increased Akt, mTOR, and p70S6K1 phosphorylation blocked by AG 1478 (EGF receptor kinase blocker). ANG II‐induced increase in [^3^H] thymidine incorporation was blocked by the inhibition of p44/42 MAPKs but not by p38 MAPK inhibition. Indeed, ANG II phosphorylated p44/42 MAPKs, which was prevented by the inhibition of the PKC and AT~1~ receptor. ANG II increased c‐fos, c‐jun, and c‐myc levels. ANG II also increased the protein levels of cyclin D1, cyclin E, cyclin‐dependent kinase (CDK) 2, and CDK4 but decreased the p21^cip1/waf1^ and p27^kip1^, CDK inhibitory proteins. These proteins were blocked by the inhibition of AT~1~ receptor, PLC/PKC, p44/42 MAPKs, EGF receptor, or tyrosine kinase. In conclusion, ANG II‐stimulated DNA synthesis is mediated by ANG II receptor‐dependent Ca^2+^/PKC and EGF receptor‐dependent PI3K/Akt/mTOR/p70S6K1 signal pathways in mouse ES cells. J. Cell. Physiol. 211: 618–629, 2007. © 2007 Wiley‐Liss, Inc.