Abstract
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 1beta-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.
Publication types
-
Research Support, Non-U.S. Gov't
-
Research Support, U.S. Gov't, P.H.S.
MeSH terms
-
Apoptosis
-
CASP8 and FADD-Like Apoptosis Regulating Protein
-
Carrier Proteins / genetics
-
Cells, Cultured
-
DNA / metabolism
-
DNA-Binding Proteins / physiology*
-
Eye Proteins*
-
Humans
-
Intracellular Signaling Peptides and Proteins*
-
Mitogen-Activated Protein Kinase 1 / physiology
-
Mitogen-Activated Protein Kinase 3
-
Mitogen-Activated Protein Kinase 8
-
Mitogen-Activated Protein Kinase 9
-
Mitogen-Activated Protein Kinases / physiology
-
NFATC Transcription Factors
-
Neovascularization, Physiologic*
-
Nerve Growth Factors*
-
Nuclear Proteins*
-
Phosphorylation
-
Promoter Regions, Genetic
-
Proteins / physiology
-
Serpins / physiology
-
Transcription Factors / physiology*
-
p38 Mitogen-Activated Protein Kinases
Substances
-
CASP8 and FADD-Like Apoptosis Regulating Protein
-
CFLAR protein, human
-
Carrier Proteins
-
DNA-Binding Proteins
-
Eye Proteins
-
Intracellular Signaling Peptides and Proteins
-
NFATC Transcription Factors
-
NFATC2 protein, human
-
Nerve Growth Factors
-
Nuclear Proteins
-
Proteins
-
Serpins
-
Transcription Factors
-
pigment epithelium-derived factor
-
DNA
-
Mitogen-Activated Protein Kinase 9
-
Mitogen-Activated Protein Kinase 1
-
Mitogen-Activated Protein Kinase 3
-
Mitogen-Activated Protein Kinase 8
-
Mitogen-Activated Protein Kinases
-
p38 Mitogen-Activated Protein Kinases