Heparin-binding epidermal growth factor-like growth factor: p91 activation, induction of plasminogen activator/plasminogen activator inhibitor, and tubular morphogenesis in human microvascular endothelial cells

Shin Ushiro, Mayumi Ono, Hiroto Izumi, Kimitoshi Kohno, Naoyuki Taniguchi, Shigeki Higashiyama, Michihiko Kuwano

研究成果: Contribution to journalArticle査読

30 被引用数 (Scopus)

抄録

Epidermal growth factor (EGF) or transforming growth factor-α (TGF-α) stimulates cell migration, proliferation and the formation of tube-like structures of human microvascular endothelial cells in culture. Heparin-binding EGF-like growth factor (HB-EGF), which shows 35% homology with EGF/ TGF-α, is a member of the EGF family, and it is ubiquitous in many tissues and organs. We examined whether or not HB-EGF induced angiogenic responses in human microvascular endothelial cells. HB-EGF inhibited the binding of 125I-EGF to the EGF receptor and induced autophosphorylation of the receptor on endothelial cells. Exogenous HB-EGF induced the loss of more than 70% of the EGF receptor from the cell surface within 30 min, with similar kinetics to that of EGF. The level of c-fos mRNA markedly increased at 30 min in response to HB-EGF as well as EGF. A gel shift assay demonstrated the activation of the transcription factor p91 by HB-EGF and EGF. This factor directly interacts with the EGF receptor and mediates the activation of c-fos gene promoter. HB-EGF enhanced the mRNA expression of tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1) mRNA. However, the enhancement of t-PA and PAI-1 by HB-EGF was less than that by EGF. Heparitinase/chlorate, which digests the heparan sulfate proteoglycan of the endothelial cell surface, restored both t-PA and PAI-1 mRNA levels in response to HB-EGF in a manner similar to that by EGF. HB-EGF at 10 ng/ml developed tube-like structures in type I collagen gel at similar levels to that of EGF at 10 ng/ml, suggesting that HB-EGF is also a potent angiogenic factor in the model system for angiogenesis. The tubulogenesis activity of HB-EGF is discussed in relation to the expression of the t-PA and PAI-1 genes.

本文言語英語
ページ(範囲)68-77
ページ数10
ジャーナルJapanese Journal of Cancer Research
87
1
DOI
出版ステータス出版済み - 1 1996
外部発表はい

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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