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.
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 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.
authors.affiliation: Medical and Bio-Material Research Center, Kangwon National University, Chunchon, Kangwon-do, Republic of Korea.
authors.forename: Young-June
authors.initials: YJ
authors.lastname: Jin
authors.forename: Jeong-Hyung
authors.initials: JH
authors.lastname: Lee
authors.forename: Young-Myeong
authors.initials: YM
authors.lastname: Kim
authors.forename: Goo Taeg
authors.initials: GT
authors.lastname: Oh
authors.forename: Hansoo
authors.initials: H
authors.lastname: Lee
mesh_terms: D049109:Cell Proliferation; D019938:Cyclin D1 / Q000378:metabolism; D019927:Cyclin E / Q000378:metabolism; D050684:E2F Transcription Factors / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D055436:Growth Differentiation Factor 15 / Q000378:metabolism*; D006460:Hemolysin Proteins; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D019927:Cyclin E; D050684:E2F Transcription Factors; C526140:GDF15 protein, human; D055436:Growth Differentiation Factor 15; D006460:Hemolysin Proteins; D018808:Transcription Factor AP-1; D019938:Cyclin D1; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases