title: ERK5 regulates basic fibroblast growth factor-induced type 1 plasminogen activator inhibitor expression and cell proliferation in lung fibroblasts.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  This study reveals a novel role for the ERK5-MEF2 cascade, linking bFGF-induced PAI-1 expression and subsequent mitogenic processes in lung fibroblasts.
authors.affiliation: Department of Pharmacology, Yeungnam University College of Medicine, 317-1 Daemyung-dong, Daegu, Republic of Korea.
authors.forename: Jung-Hwa
authors.initials: JH
authors.lastname: Han
authors.affiliation: Department of Pharmacology, Yeungnam University College of Medicine, 317-1 Daemyung-dong, Daegu, Republic of Korea.
authors.forename: Ae-Rang
authors.initials: AR
authors.lastname: Hwang
authors.affiliation: Department of Pharmacology, Yeungnam University College of Medicine, 317-1 Daemyung-dong, Daegu, Republic of Korea.
authors.forename: Dae-Hwan
authors.initials: DH
authors.lastname: Nam
authors.affiliation: Department of Pharmacology, Yeungnam University College of Medicine, 317-1 Daemyung-dong, Daegu, Republic of Korea.
authors.forename: Suji
authors.initials: S
authors.lastname: Kim
authors.affiliation: Department of Pharmacology, Yeungnam University College of Medicine, 317-1 Daemyung-dong, Daegu, Republic of Korea.
authors.forename: Hyoung Chul
authors.initials: HC
authors.lastname: Choi
authors.affiliation: Department of Microbiology, Ewha Womans University School of Medicine, 911-1 Mok-dong, Seoul, Republic of Korea. Electronic address: jlim19@ewha.ac.kr.
authors.forename: Jae Hyang
authors.initials: JH
authors.lastname: Lim
authors.affiliation: Department of Pharmacology, Yeungnam University College of Medicine, 317-1 Daemyung-dong, Daegu, Republic of Korea. Electronic address: changhoon_woo@yu.ac.kr.
authors.forename: Chang-Hoon
authors.initials: CH
authors.lastname: Woo
mesh_terms: D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects* / Q000235:genetics; D016222:Fibroblast Growth Factor 2 / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D064326:MEF2 Transcription Factors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D048054:Mitogen-Activated Protein Kinase 7 / Q000235:genetics / Q000378:metabolism*; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis* / Q000235:genetics; D011401:Promoter Regions, Genetic; D011658:Pulmonary Fibrosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D058258:Serpin E2 / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D064326:MEF2 Transcription Factors; D017395:Plasminogen Activator Inhibitor 1; D034741:RNA, Small Interfering; C051321:SERPINE1 protein, human; D058258:Serpin E2; C511869:Serpine2 protein, mouse; D016222:Fibroblast Growth Factor 2; D048054:Mitogen-Activated Protein Kinase 7
keywords: ERK5; Fibroblasts; PAI-1; Pulmonary fibrosis; bFGF