title: Nuclear factor of activated T cells balances angiogenesis activation and inhibition.
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.
authors.affiliation: Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
authors.forename: Tetiana A
authors.initials: TA
authors.lastname: Zaichuk
authors.forename: Emelyn H
authors.initials: EH
authors.lastname: Shroff
authors.forename: Rebekah
authors.initials: R
authors.lastname: Emmanuel
authors.forename: Stephanie
authors.initials: S
authors.lastname: Filleur
authors.forename: Thomas
authors.initials: T
authors.lastname: Nelius
authors.forename: Olga V
authors.initials: OV
authors.lastname: Volpert
mesh_terms: D017209:Apoptosis; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002352:Carrier Proteins / Q000235:genetics; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000502:physiology*; D005136:Eye Proteins; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D019950:Mitogen-Activated Protein Kinase 1 / Q000502:physiology; D048052:Mitogen-Activated Protein Kinase 3; D048055:Mitogen-Activated Protein Kinase 8; D048056:Mitogen-Activated Protein Kinase 9; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D050778:NFATC Transcription Factors; D018919:Neovascularization, Physiologic; D009414:Nerve Growth Factors; D009687:Nuclear Proteins; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011506:Proteins / Q000502:physiology; D015843:Serpins / Q000502:physiology; D014157:Transcription Factors / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases; D000099174:Pigment Epithelium-Derived Factor
chemical_list: D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002352:Carrier Proteins; D004247:DNA; D004268:DNA-Binding Proteins; D005136:Eye Proteins; D047908:Intracellular Signaling Peptides and Proteins; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048055:Mitogen-Activated Protein Kinase 8; D048056:Mitogen-Activated Protein Kinase 9; D020928:Mitogen-Activated Protein Kinases; D050778:NFATC Transcription Factors; D009414:Nerve Growth Factors; D009687:Nuclear Proteins; D011506:Proteins; D015843:Serpins; D014157:Transcription Factors; D048051:p38 Mitogen-Activated Protein Kinases; D000099174:Pigment Epithelium-Derived Factor; C506386:CFLAR protein, human; C494006:NFATC2 protein, human