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

Young June Jin, Jeong Hyung Lee, Young Myeong Kim, Goo Taeg Oh, Hansoo Lee

Research output: Contribution to journalArticlepeer-review

46 Scopus citations

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.

Original languageEnglish
Pages (from-to)1485-1495
Number of pages11
JournalCellular Signalling
Volume24
Issue number8
DOIs
StatePublished - Aug 2012

Bibliographical note

Funding Information:
We thank Elaine Por for corrections of the manuscript. This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (MEST) ( 2011–0024380 ). This work was also supported by Mid-career Researcher Program through a NRF grant funded by the MEST ( 2009–0054632 ).

Keywords

  • Cell cycle
  • Cell proliferation
  • Cyclin
  • Endothelial cell
  • Macrophage inhibitory cytokine-1
  • Signaling

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