Induction of hepatocyte growth factor expression by maleic acid in human fibroblasts through MAPK activation

Takahiro Motoki, Yoshihiro Sugiura, Yohsuke Matsumoto, Tomoe Tsuji, Satoshi Kubota, Masaharu Takigawa, Eiichi Gohda

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)


Carboxylic acids have various biological activities and play critical roles in cellular metabolic pathways such as the tricarboxylic acid (TCA) cycle. It has been shown that some carboxylic acids induce cell proliferation and production of cytokines or growth factors. However, there have been no reports on effects of carboxylic acids on hepatocyte growth factor (HGF) expression. In this study, we found that only maleic acid among various carboxylic acids examined markedly induced HGF production from human dermal fibroblasts. Maleic acid also induced HGF production from human lung fibroblasts and neuroblastoma cells. The stimulatory effect was accompanied by upregulation of HGF gene expression. Increase in phosphorylation of extracellular signal-regulated protein kinase (ERK) and c-Jun N-terminal kinase (JNK) but not in phosphorylation of p38 was observed from 6 h and up to 24 h after maleic acid addition. The ERK kinase inhibitor PD98059 and the JNK inhibitor SP600125 potently inhibited maleic acid-induced HGF production, while the p38 inhibitor SB203580 did not significantly inhibit the production. The protein synthesis inhibitor cycloheximide completely inhibited upregulation of HGF mRNA induced by maleic acid but superinduced HGF mRNA expression upregulated by 12-O-tetradecanoylphorbol 13-acetate (TPA). These results suggest that maleic acid indirectly induced HGF expression from human dermal fibroblasts through activation of ERK and JNK and that de novo protein synthesis is required for maleic acid-induced upregulation of HGF mRNA.

Original languageEnglish
Pages (from-to)1465-1476
Number of pages12
JournalJournal of Cellular Biochemistry
Issue number4
Publication statusPublished - Jul 1 2008


  • Carboxylic acids
  • HGF
  • MAPK
  • Maleic acid

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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