Macrophage inhibitory cytokine-1 stimulates proliferation of human umbilical vein endothelial cells by up-regulating cyclins D1 and E through the PI3K/Akt-, ERK-, and JNK-dependent AP-1 and E2F activation signaling pathways
Macrophage inhibitory cytokine-1 stimulates proliferation of human umbilical vein endothelial cells by up-regulating cyclins D1 and E through the PI3K/Akt-, ERK-, and JNK-dependent AP-1 and E2F activation signaling pathways
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DOI：
10.1016/j.cellsig.2012.03.014
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发表时间：
2012-08-01
影响因子：
4.8
通讯作者：
Lee, Hansoo
中科院分区：
文献类型：
--
作者：
Jin, Young-June;Lee, Jeong-Hyung;Lee, Hansoo
巨噬细胞抑制性细胞因子-1（MIC-1）与人类恶性肿瘤高度相关，并已被认为参与肿瘤血管生成。在本研究中，我们检查了MIC-1对内皮细胞增殖的影响，以确认MIC-1的血管生成促进作用。MIC-1处理加速了人脐静脉内皮细胞（HUVEC）细胞周期中G（1）期的进展，导致细胞增殖率增加。MIC-1增加了细胞周期蛋白D1和E的水平，而不改变细胞周期蛋白依赖性激酶（CDK）抑制剂的水平，从而增加了CDK的蛋白激酶活性和随后的Rb蛋白磷酸化，随后是E2 F的核转位。MIC-1诱导的细胞周期蛋白D1和E的表达是由AP-1和E2 F-1转录因子介导的，在AP-1成员中，c-Jun和JunD似乎参与MIC-1依赖的细胞周期蛋白D1基因的转录。此外，发现PI 3 K/Akt、JNK和ERK途径介导MIC-1诱导的HUVECs中细胞周期蛋白D1表达。重要的是，从MIC-1转基因小鼠中分离的肺内皮细胞相对于其野生型对应物显示出更高的增殖率和细胞周期蛋白D1和E水平。这些结果表明，癌细胞分泌的MIC-1通过PI 3 K/Akt、JNK和ERK信号通路增强AP-1和E2 F依赖的G（1）细胞周期蛋白表达，从而刺激内皮细胞增殖，可能导致肿瘤血管生成增强。(C)2012 Elsevier Inc. All rights reserved.
Macrophage inhibitory cytokine-1 (MIC-1) is highly associated with malignant human cancers and has been suggested to be involved in tumor angiogenesis. In the present study, we examined the effect of MIC-1 on endothelial cell proliferation to confirm the angiogenesis-promoting role of MIC-1. MIC-1 treatment accelerated progression of the G(1) stage in the cell cycle of human umbilical vein endothelial cells (HUVECs), leading to an increased cell proliferation rate. MIC-1 augmented the levels of cyclins D1 and E without altering the levels of cyclin-dependent kinase (CDK) inhibitors, thereby increasing protein kinase activity of CDKs and subsequent phosphorylation of the Rb protein followed by nuclear translocation of E2F. MIC-1-induced expression of cyclins D1 and E was mediated by AP-1 and E2F-1 transcription factors, and among the AP-1 members, c-Jun and JunD appeared to participate in MIC-1-dependent transcription of the cyclin D1 gene. Additionally, the PI3K/Akt, JNK, and ERK pathways were found to mediate MIC-1-induced cyclin D1 expression in HUVECs. Importantly, lung endothelial cells isolated from MIC-1 transgenic mouse displayed a higher proliferation rate and cyclin D1 and E levels relative to their wild-type counterparts. These results suggest that MIC-1 secreted from cancer cells stimulates endothelial cell proliferation by enhancing AP-1- and E2F-dependent expression of G(1) cyclins via PI3K/Akt, JNK, and ERK signaling pathways, potentially leading to enhanced tumor angiogenesis. (C) 2012 Elsevier Inc. All rights reserved.