Zhang Qiang, Liu Shu-Hui, Erikson Mark, Lewis Martyn, Unemori Elaine
Connetics Corporation, 3400 West Bayshore Rd., Palo Alto, California 94303, USA.
J Cell Biochem. 2002;85(3):536-44. doi: 10.1002/jcb.10150.
The reproductive hormone, relaxin, is structurally similar to insulin and insulin-like growth factor (IGF). Although a number of cellular responses to relaxin have been described, intracellular signaling mechanisms that link relaxin receptor engagement to alterations in gene expression remain uncharacterized. In the present study, relaxin treatment of a well-characterized target, human endometrial stromal cells, resulted in rapid activation of p42/44 mitogen-activated protein (MAP) kinase, as well as of MAPK (or ERK) kinase (MEK). Using a selective chemical inhibitor of MEK, it was further demonstrated that MEK phosphorylation is critical for relaxin-induced MAP kinase activation. Relaxin treatment also induced MAP kinase activation in THP-1 monocytic cells and in human smooth muscle cells, indicating that it may be a major signaling transducer utilized by the relaxin receptor. In contrast to insulin or IGF-1, relaxin did not trigger the PI 3-kinase/Akt pathway, perhaps accounting in part for relaxin's unique biological profile. Relaxin was also found to cause activation of the transcription factor CREB, a substrate of the MAP kinase pathway. Finally, activation of the MAP kinase pathway was shown to be essential for optimal stimulation of expression of the gene for vascular endothelial growth factor.
生殖激素松弛素在结构上与胰岛素及胰岛素样生长因子（IGF）相似。尽管已经描述了许多细胞对松弛素的反应，但将松弛素受体结合与基因表达改变联系起来的细胞内信号传导机制仍未明确。在本研究中，用松弛素处理特征明确的靶细胞——人子宫内膜基质细胞，导致p42/44丝裂原活化蛋白（MAP）激酶以及MAP激酶（或细胞外信号调节激酶，ERK）激酶（MEK）迅速激活。使用MEK的选择性化学抑制剂进一步证明，MEK磷酸化对于松弛素诱导的MAP激酶激活至关重要。松弛素处理还在THP-1单核细胞和人平滑肌细胞中诱导了MAP激酶激活，表明它可能是松弛素受体利用的主要信号转导分子。与胰岛素或IGF-1不同，松弛素不会触发PI 3-激酶/Akt途径，这可能部分解释了松弛素独特的生物学特性。还发现松弛素会导致转录因子CREB激活，CREB是MAP激酶途径的底物。最后，MAP激酶途径的激活被证明对于最佳刺激血管内皮生长因子基因的表达至关重要。
