title: Tumor-Derived Factors and Reduced p53 Promote Endothelial Cell Centrosome Over-Duplication.
abstract: Approximately 30% of tumor endothelial cells have over-duplicated (>2) centrosomes, which may contribute to abnormal vessel function and drug resistance. Elevated levels of vascular endothelial growth factor A induce excess centrosomes in endothelial cells, but how other features of the tumor environment affect centrosome over-duplication is not known. To test this, we treated endothelial cells with tumor-derived factors, hypoxia, or reduced p53, and assessed centrosome numbers. We found that hypoxia and elevated levels of bone morphogenetic protein 2, 6 and 7 induced excess centrosomes in endothelial cells through BMPR1A and likely via SMAD signaling. In contrast, inflammatory mediators IL-8 and lipopolysaccharide did not induce excess centrosomes. Finally, down-regulation in endothelial cells of p53, a critical regulator of DNA damage and proliferation, caused centrosome over-duplication. Our findings suggest that some tumor-derived factors and genetic changes in endothelial cells contribute to excess centrosomes in tumor endothelial cells.
authors.affiliation: Curriculum in Genetics and Molecular Biology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Zhixian
authors.initials: Z
authors.lastname: Yu
authors.affiliation: Department of Biology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Mouillesseaux
authors.affiliation: Department of Biology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Erich J
authors.initials: EJ
authors.lastname: Kushner
authors.affiliation: Curriculum in Genetics and Molecular Biology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.|Department of Biology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.|McAllister Heart Institute, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Victoria L
authors.initials: VL
authors.lastname: Bautch
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D018385:Centrosome / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology* / Q000648:ultrastructure; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000098:blood supply / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000235:genetics*
chemical_list: D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53