Specificity, diversity, and convergence in VEGF and TNF-α signaling events leading to tissue factor upregulation via EGR-1 in endothelial cells

D. Mechtcheriakova, G. Schabbauer, M. Lucerna, M. Clauss, R. De Martin, B. R. Binder, E. Hofer

Research output: Contribution to journalArticle

167 Scopus citations

Abstract

Tissue factor (TF7) has been shown to be up-regulated in endothelial cells by the inflammatory cytokine tumor necrosis factor α (TNF-α) as well as by the main angiogenic factor VEGF. Since both stimuli induce the transcription factor EGR-1, which is critically involved in TF gene regulation, we used EGR-1-dependent TF induction as a model to identify potential cross-talks between the various signal transduction cascades initiated by VEGF and TNF-α. The data show that at the MAP kinase level, VEGF mainly activates ERK1/2 and p38 MAP kinases in human endothelial cells. TNF-α is able to activate all three MAP kinase cascades as well as the classical inflammatory IκB/NFκB pathway. Furthermore, the MEK/ERK module of MAP kinases appears to act as the convergence point of VEGF- and TNF-α-initiated signaling cascades, which lead to the activation of EGR-1 and subsequent TF expression, whereas the upstream signals are distinct. We found that induction of TF by VEGF via EGR-1 is strongly PKC dependent. The TNF-αinitiated MEK/ERK cascade connected to EGR-1 and TF expression is clearly less sensitive to PKC inhibition. TNF-α-mediated activation of MEK/ERK and EGR-1 can be blocked by adenoviral expression of a dominant negative mutant of IKK2, whereas the VEGF signaling pathway is unaffected. Thus, our data demonstrate a new link between the classical inflammatory IKK/IκB and the MEK/ERK cascades triggered by TNF-α. The additional finding that EGF induces ERK and EGR-1 in a PKC-independent manner and that this signal is not sufficient to up-regulate TF emphasizes the importance of a VEGF-specific signaling pattern for the induction of TF.

Original languageEnglish (US)
Pages (from-to)230-242
Number of pages13
JournalFASEB Journal
Volume15
Issue number1
DOIs
StatePublished - Jan 31 2001
Externally publishedYes

Keywords

  • Angiogenic growth factors
  • Endothelium
  • Inflammatory cytokines
  • MAP kinases
  • Tissue factor

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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