title: BAZF, a novel component of cullin3-based E3 ligase complex, mediates VEGFR and Notch cross-signaling in angiogenesis.
abstract: Angiogenic homeostasis is maintained by a balance between vascular endothelial growth factor (VEGF) and Notch signaling in endothelial cells (ECs). We screened for molecules that might mediate the coupling of VEGF signal transduction with down-regulation of Notch signaling, and identified B-cell chronic lymphocytic leukemia/lymphoma6-associated zinc finger protein (BAZF). BAZF was induced by VEGF-A in ECs to bind to the Notch signaling factor C-promoter binding factor 1 (CBF1), and to promote the degradation of CBF1 through polyubiquitination in a CBF1-cullin3 (CUL3) E3 ligase complex. BAZF disruption in vivo decreased endothelial tip cell number and filopodia protrusion, and markedly abrogated vascular plexus formation in the mouse retina, overlapping the retinal phenotype seen in response to Notch activation. Further, impaired angiogenesis and capillary remodeling were observed in skin-wounded BAZF(-/-) mice. We therefore propose that BAZF supports angiogenic sprouting via BAZF-CUL3-based polyubiquitination-dependent degradation of CBF1 to down-regulate Notch signaling.
authors.affiliation: Department of Biochemistry and Molecular Genetics, Ehime University, Ehime, Japan.
authors.forename: Hidetaka
authors.initials: H
authors.lastname: Ohnuki
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Inoue
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Takemori
authors.forename: Hironao
authors.initials: H
authors.lastname: Nakayama
authors.forename: Tomohisa
authors.initials: T
authors.lastname: Sakaue
authors.forename: Shinji
authors.initials: S
authors.lastname: Fukuda
authors.forename: Daisuke
authors.initials: D
authors.lastname: Miwa
authors.forename: Eiji
authors.initials: E
authors.lastname: Nishiwaki
authors.forename: Masahiko
authors.initials: M
authors.lastname: Hatano
authors.forename: Takeshi
authors.initials: T
authors.lastname: Tokuhisa
authors.forename: Yaeta
authors.initials: Y
authors.lastname: Endo
authors.forename: Masato
authors.initials: M
authors.lastname: Nose
authors.forename: Shigeki
authors.initials: S
authors.lastname: Higashiyama
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D002450:Cell Communication; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D044842:Cullin Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D047468:Immunoprecipitation; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009024:Morphogenesis; D018919:Neovascularization, Physiologic; D020411:Oligonucleotide Array Sequence Analysis; D025821:Polyubiquitin / Q000378:metabolism; D011554:Pseudopodia / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D051880:Receptors, Notch / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D012160:Retina / Q000166:cytology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D012867:Skin / Q000293:injuries / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014945:Wound Healing
chemical_list: C486398:BCL6B protein, human; C113027:Bcl6b protein, mouse; D015415:Biomarkers; C503645:CUL3 protein, human; D044842:Cullin Proteins; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; C497570:RBPJ protein, human; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D051880:Receptors, Notch; D012097:Repressor Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D025821:Polyubiquitin; D008156:Luciferases; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2