The Journal of Experimental Medicine
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Published 7 June 2004. doi:10.1084/jem.20040474
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 199, Number 11, 1513-1522
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Nuclear Factor of Activated T Cells Balances Angiogenesis Activation and Inhibition

Tetiana A. Zaichuk1, Emelyn H. Shroff1, Rebekah Emmanuel1,2, Stephanie Filleur1, Thomas Nelius1,3, and Olga V. Volpert1

1 Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611
2 Yale University, New Haven, CT 06520
3 Department of Urology, Otto-von-Guericke-University Magdeburg, D-39120 Magdeburg, Germany

Address correspondence to Olga Volpert, Dept. of Urology, Northwestern University Feinberg School of Medicine, 300 E. Superior St., Tarry Research Building, Rm. 16-761, Chicago, IL 60611. Phone: (312) 503-5934; Fax: (312) 908-7275; email: olgavolp{at}northwestern.edu

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 NH2-terminal kinases (JNKs) as essential upstream regulators of NFAT activity in angiogenesis. We distinguished JNK-2 as responsible 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 1ß–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.

Key Words: regulatory kinases • angiogenesis inhibitors • signaling cross-talk • transcription factors • pigment epithelial–derived factor

Abbreviations used in this paper: bFGF, basic fibroblast growth factor; c-FLIP, cellular Fas-associated death domain–like interleukin 1ß–converting enzyme inhibitory protein; ChIP, chromatin immunoprecipitation; EC, endothelial cell; EMSA, electrophoresis mobility shift assay; HUVEC, human umbilical vein endothelial cell; JNK, c-Jun NH2-terminal kinase; MAPK, mitogen-activated protein kinase; PAb, polyclonal antibody; PEDF, pigment epithelial–derived factor; TUNEL, TdT-mediated dUTP nick-end labeling; VEGF, vascular endothelial cell growth factor.


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