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, Matthias Clauss, R. De Martin, B. R. Binder, E. Hofer

Research output: Contribution to journalArticle

166 Citations (Scopus)

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 - 2001
Externally publishedYes

Fingerprint

tumor necrosis factors
Endothelial cells
Thromboplastin
mitogen-activated protein kinase
Vascular Endothelial Growth Factor A
endothelial cells
Up-Regulation
Endothelial Cells
Tumor Necrosis Factor-alpha
Mitogen-Activated Protein Kinase Kinases
Phosphotransferases
Early Growth Response Transcription Factors
IKappaB kinase
Chemical activation
Signal transduction
MAP Kinase Signaling System
Angiogenesis Inducing Agents
Extracellular Signal-Regulated MAP Kinases
p38 Mitogen-Activated Protein Kinases
tissues

Keywords

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

ASJC Scopus subject areas

  • Agricultural and Biological Sciences (miscellaneous)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry
  • Cell Biology

Cite this

Specificity, diversity, and convergence in VEGF and TNF-α signaling events leading to tissue factor upregulation via EGR-1 in endothelial cells. / Mechtcheriakova, D.; Schabbauer, G.; Lucerna, M.; Clauss, Matthias; De Martin, R.; Binder, B. R.; Hofer, E.

In: FASEB Journal, Vol. 15, No. 1, 2001, p. 230-242.

Research output: Contribution to journalArticle

Mechtcheriakova, D. ; Schabbauer, G. ; Lucerna, M. ; Clauss, Matthias ; De Martin, R. ; Binder, B. R. ; Hofer, E. / Specificity, diversity, and convergence in VEGF and TNF-α signaling events leading to tissue factor upregulation via EGR-1 in endothelial cells. In: FASEB Journal. 2001 ; Vol. 15, No. 1. pp. 230-242.
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T1 - Specificity, diversity, and convergence in VEGF and TNF-α signaling events leading to tissue factor upregulation via EGR-1 in endothelial cells

AU - Mechtcheriakova, D.

AU - Schabbauer, G.

AU - Lucerna, M.

AU - Clauss, Matthias

AU - De Martin, R.

AU - Binder, B. R.

AU - Hofer, E.

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AB - 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.

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