Kanno Y, Ishisaki A, Yoshida M, Tokuda H, Numata O, Kozawa O
Department of Pharmacology, Gifu University School of Medicine, Japan.
Horm Metab Res. 2005 Mar;37(3):140-5. doi: 10.1055/s-2005-861291.
We previously reported that transforming growth factor-beta (TGF-beta) activates p44/p42 mitogen-activated protein (MAP) kinase and p38 MAP kinase, resulting in the stimulation of vascular endothelial growth factor (VEGF) synthesis in osteoblast-like MC3T3-E1 cells. In the present study, we investigated the involvement of stress-activated protein kinase/c- Jun N-terminal kinase (SAPK/JNK), another member of the MAP kinase superfamily, in TGF-beta-induced VEGF synthesis in these cells. TGF-beta markedly induced SAPK/JNK phosphorylation. SP600125, a specific inhibitor of SAPK/JNK, markedly reduced TGF-beta-induced VEGF synthesis. SP600125 suppressed TGF-beta-induced SAPK/JNK phosphorylation. PD98059, an inhibitor of upstream kinase of p44/p42 MAP kinase and SB203580, an inhibitor of p38 MAP kinase, each failed to reduce TGF-beta-induced SAPK/JNK phosphorylation. A combination of SP600125 and PD98059 or SP600125 and SB203580 suppressed TGF-beta-stimulated VEGF synthesis in an additive manner. These results strongly suggest that TGF-beta activates SAPK/JNK in osteoblasts, and that SAPK/JNK plays a role in addition to p42/p44 MAP kinase and p38 MAP kinase in TGF-beta-induced VEGF synthesis.
我们先前报道，转化生长因子-β（TGF-β）可激活p44/p42丝裂原活化蛋白（MAP）激酶和p38 MAP激酶，从而刺激成骨样MC3T3-E1细胞中血管内皮生长因子（VEGF）的合成。在本研究中，我们调查了MAP激酶超家族的另一个成员——应激激活蛋白激酶/c-Jun氨基末端激酶（SAPK/JNK）在TGF-β诱导这些细胞合成VEGF过程中的作用。TGF-β显著诱导SAPK/JNK磷酸化。SAPK/JNK的特异性抑制剂SP600125显著降低了TGF-β诱导的VEGF合成。SP600125抑制了TGF-β诱导的SAPK/JNK磷酸化。p44/p42 MAP激酶上游激酶的抑制剂PD98059和p38 MAP激酶的抑制剂SB203580均未能降低TGF-β诱导的SAPK/JNK磷酸化。SP600125与PD98059或SP600125与SB203580联合使用，以相加的方式抑制了TGF-β刺激的VEGF合成。这些结果强烈表明，TGF-β在成骨细胞中激活SAPK/JNK，并且在TGF-β诱导的VEGF合成中，SAPK/JNK除了p42/p44 MAP激酶和p38 MAP激酶外也发挥作用。
