Nuclear factor of activated T cells balances angiogenesis activation and inhibition

Tetiana A. Zaichuk, Emelyn H. Shroff, Rebekah Emmanuel, Stephanie Filleur, Thomas Nelius, Olga V. Volpert*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

118 Scopus citations


It has been demonstrated that vascular endothelial cell growth factor (VEGF) induction of angiogenesis requires activation of the nuclear factor of activated T cells (NFAT). We show that NFATc2 is also activated by basic fibroblast growth factor and blocked by the inhibitor of angiogenesis pigment epithelial-derived factor (PEDF). This suggests a pivotal role for this transcription factor as a convergence point between stimulatory and inhibitory signals in the regulation of angiogenesis. We identified c-Jun NH 2-terminal kinases (JNKs) as essential upstream regulators of NFAT activity in angiogenesis. We distinguished JNK-2 as for NFATc2 cytoplasmic retention by PEDF and JNK-1 and JNK-2 as mediators of PEDF-driven NFAT nuclear export. We identified a novel NFAT target, caspase-8 inhibitor cellular Fas-associated death domain-like interleukin 1β-converting enzyme inhibitory protein (c-FLIP), whose expression was coregulated by VEGF and PEDF. Chromatin immunoprecipitation showed VEGF-dependent increase of NFATc2 binding to the c-FLIP promoter in vivo, which was attenuated by PEDF. We propose that one possible mechanism of concerted angiogenesis regulation by activators and inhibitors may be modulation of the endothelial cell apoptosis via c-FLIP controlled by NFAT and its upstream regulator JNK.

Original languageEnglish (US)
Pages (from-to)1513-1522
Number of pages10
JournalJournal of Experimental Medicine
Issue number11
StatePublished - Jun 7 2004


  • Angiogenesis inhibitors
  • Pigment epithelial-derived factor
  • Regulatory kinases
  • Signaling cross-talk
  • Transcription factors

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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