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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

Title
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
Authors
Jin Y.-J.Lee J.-H.Kim Y.-M.Oh G.T.Lee H.
Ewha Authors
오구택
SCOPUS Author ID
오구택scopus
Issue Date
2012
Journal Title
Cellular Signalling
ISSN
0898-6568JCR Link
Citation
vol. 24, no. 8, pp. 1485 - 1495
Indexed
SCI; SCIE; SCOPUS WOS scopus
Abstract
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 G1 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 G1 cyclins via PI3K/Akt, JNK, and ERK signaling pathways, potentially leading to enhanced tumor angiogenesis. © 2012 Elsevier Inc.
DOI
10.1016/j.cellsig.2012.03.014
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자연과학대학 > 생명과학전공 > Journal papers
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