Han Ho Jae, Han Ji Yeon, Heo Jung Sun, Lee Sang Hun, Lee Min Young, Kim Yun Hee
Department of Veterinary Physiology, Biotherapy Human Resources Center, College of Veterinary Medicine, Chonnam National University, Gwangju, Korea.
J Cell Physiol. 2007 Jun;211(3):618-29. doi: 10.1002/jcp.20967.
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+), and translocated PKC alpha, delta, and zeta 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.
研究了血管紧张素II（ANG II）对小鼠胚胎干细胞（ES细胞）增殖的影响。ANG II以时间（>4小时）和剂量（>10(-9) M）依赖性方式增加[（3）H]胸苷掺入。ANG II诱导的[（3）H]胸苷掺入增加被血管紧张素II 1型（AT(1)）受体抑制所阻断，但未被血管紧张素II 2型（AT(2)）受体抑制所阻断，且AT(1)受体有表达。ANG II增加肌醇磷酸形成和Ca(2+)，并使蛋白激酶Cα、δ和ζ转位至膜组分。因此，磷脂酶C/蛋白激酶C的抑制抑制了ANG II诱导的[（3）H]胸苷掺入增加。表皮生长因子受体激酶或酪氨酸激酶的抑制阻止了ANG II诱导的[（3）H]胸苷掺入增加。ANG II使表皮生长因子受体磷酸化并增加Akt、mTOR和p70S6K1磷酸化，AG 1478（表皮生长因子受体激酶阻滞剂）可阻断此过程。ANG II诱导的[（3）H]胸苷掺入增加被p44/42丝裂原活化蛋白激酶抑制所阻断，但未被p38丝裂原活化蛋白激酶抑制所阻断。实际上，ANG II使p44/42丝裂原活化蛋白激酶磷酸化，蛋白激酶C和AT(1)受体的抑制可阻止此过程。ANG II增加c-fos、c-jun和c-myc水平。ANG II还增加细胞周期蛋白D1、细胞周期蛋白E、细胞周期蛋白依赖性激酶（CDK）2和CDK4的蛋白水平，但降低p21(cip1/waf1)和p27(kip1)这两种CDK抑制蛋白的水平。这些蛋白的变化被AT(1)受体、磷脂酶C/蛋白激酶C、p44/42丝裂原活化蛋白激酶、表皮生长因子受体或酪氨酸激酶的抑制所阻断。总之，在小鼠ES细胞中，ANG II刺激的DNA合成由ANG II受体依赖性Ca(2+)/蛋白激酶C和表皮生长因子受体依赖性PI3K/Akt/mTOR/p70S6K1信号通路介导。
