title: Depletion of the novel protein PHACTR-1 from human endothelial cells abolishes tube formation and induces cell death receptor apoptosis.
abstract: Using suppression subtractive hybridisation (SSH), we identified a hitherto unreported gene PHACTR-1 (Phosphatase Actin Regulating Protein-1) in Human Umbilical Vascular Endothelial Cells (HUVECs). PHACTR-1 is an actin and protein phosphatase 1 (PP1) binding protein which is reported to be highly expressed in brain and which controls PP1 activity and F-actin remodelling. We have also reported that its expression is dependent of Vascular Endothelial Growth Factor (VEGF-A(165)). To study its function in endothelial cells, we used a siRNA strategy against PHACTR-1. PHACTR-1 siRNA-treated HUVECs showed a major impairment of tube formation and stabilisation. PHACTR-1 depletion triggered apoptosis through death receptors DR4, DR5 and FAS, which was reversed using death receptor siRNAs or with death receptor-dependent caspase-8 siRNA. Our findings suggest that PHACTR-1 is likely to be a key regulator of endothelial cell function properties. Because of its central role in the control of tube formation and endothelial cell survival, PHACTR-1 may represent a new target for the development of anti-angiogenic therapy.
authors.affiliation: Université Paris Descartes, Sorbonne Paris Cité, CNRS UMR 8601, Laboratoire de chimie et biochimie pharmacologiques et toxicologiques, 45 rue des Saints-Pères, 75006 Paris, France.
authors.forename: Rafika
authors.initials: R
authors.lastname: Jarray
authors.forename: Barbara
authors.initials: B
authors.lastname: Allain
authors.forename: Lucia
authors.initials: L
authors.lastname: Borriello
authors.forename: Denis
authors.initials: D
authors.lastname: Biard
authors.forename: Ali
authors.initials: A
authors.lastname: Loukaci
authors.forename: Jérôme
authors.initials: J
authors.lastname: Larghero
authors.forename: Réda
authors.initials: R
authors.lastname: Hadj-Slimane
authors.forename: Christiane
authors.initials: C
authors.lastname: Garbay
authors.forename: Yves
authors.initials: Y
authors.lastname: Lepelletier
authors.forename: Françoise
authors.initials: F
authors.lastname: Raynaud
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D034741:RNA, Small Interfering; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism
chemical_list: D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D019014:fas Receptor