ERK5 regulates basic fibroblast growth factor-induced type 1 plasminogen activator inhibitor expression and cell proliferation in lung fibroblasts
- 주제(키워드) bFGF , ERK5 , Fibroblasts , PAI-1 , Pulmonary fibrosis
- 등재 SCIE, SCOPUS
- 발행기관 Elsevier Inc.
- 발행년도 2015
- 총서유형 Journal
- URI http://www.dcollection.net/handler/ewha/000000118272
- 본문언어 영어
- Published As http://dx.doi.org/10.1016/j.lfs.2015.05.006
- 저작권 이화여자대학교 논문은 저작권에 의해 보호받습니다.
초록/요약
Aims: bFGF is a potent mitogen of cells associated with fibrosis. Although ERK5 has been reported to play roles in the development of fibrosis, its roles in regulating bFGF-induced fibrotic responses are not understood, especially in lung fibroblasts. The authors investigated the role of ERK5 in bFGF induction of cell proliferation and in induction of PAI-1, a critical regulator of the pathological features of fibrosis, in lung fibroblasts. Main methods: The role played by ERK5 in bFGF-induced PAI-1 expression was elucidated by perturbing the ERK5 signaling pathway using a specific chemical inhibitor and siRNA of ERK5. The effects of ERK5 signal perturbation on PAI-1 expression were measured at multiple levels by Q-PCR, immunoblotting, ELISA, and reporter gene analysis. The role of MEF2 in bFGF-induced activation of PAI-1 promoter activity via ERK5 was measured using a biotin-labeled DNA pull-down assay, and the effects of ERK5 on the mitogenic effects of bFGF were assessed using a MTT assay. Key findings: In both primary human lung fibroblast and lung fibroblast cell lines, inhibition of ERK5 blocked bFGF-induced PAI-1 expression at both mRNA and protein levels and inhibited bFGF-induced PAI-1 promoter activity induction by bFGF. Upon stimulation with bFGF, MEF2 directly bound to the consensus sequence of the MEF2 binding site in the PAI-1 promoter. In addition, bFGF-induced PAI-1 up-regulation was inhibited by MEF2 siRNA, and bFGF-induced fibroblast proliferation was blocked by inhibiting ERK5. Significance: This study reveals a novel role for the ERK5-MEF2 cascade, linking bFGF-induced PAI-1 expression and subsequent mitogenic processes in lung fibroblasts. © 2015 Elsevier Inc. All rights reserved.
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