title: Protein kinase D2 and heat shock protein 90 beta are required for BCL6-associated zinc finger protein mRNA stabilization induced by vascular endothelial growth factor-A.
abstract: Vascular endothelial growth factor (VEGF) is a major angiogenic factor that activates pro-angiogenic molecules to generate new vessels. Recently, we identified a VEGF-A-induced pro-angiogenic gene, BCL-6 associated zinc finger protein (BAZF), in endothelial cells. BAZF interacts with CBF1, a transcriptional regulator of Notch signaling, and downregulates Notch signaling by inducing the degradation of CBF1. A signal inhibition assay with a combination of chemical inhibitors and siRNA revealed that the protein kinase D (PRKD) family, mainly PRKD2, mediated BAZF gene expression by VEGF-A stimulation. A luciferase reporter assay showed that the promoter activity of the BAZF gene was unchanged by VEGF-A stimulation. However, we found that the stability of BAZF mRNA increased in a VEGF-A/PRKD2-dependent manner. In further studies to investigate the underlying mechanism, we successfully identified heat shock protein 90 beta (HSP90β) as a molecule that interacts with and stabilizes BAZF mRNA following VEGF-A/PRKD2 activation. These data suggest that HSP90β may positively regulate angiogenesis, not only as a protein chaperone, but also as an mRNA stabilizer for pro-angiogenic genes, such as BAZF, in a PRKD2 activity-dependent manner.
authors.affiliation: Department of Biochemistry and Molecular Genetics, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime 791-0295, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Miwa
authors.forename: Tomohisa
authors.initials: T
authors.lastname: Sakaue
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Inoue
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Takemori
authors.forename: Maki
authors.initials: M
authors.lastname: Kurokawa
authors.forename: Shinji
authors.initials: S
authors.lastname: Fukuda
authors.forename: Kazuya
authors.initials: K
authors.lastname: Omi
authors.forename: Katsutoshi
authors.initials: K
authors.lastname: Goishi
authors.forename: Shigeki
authors.initials: S
authors.lastname: Higashiyama
mesh_terms: D015153:Blotting, Western; D015180:Electrophoresis, Gel, Two-Dimensional; D005786:Gene Expression Regulation / Q000502:physiology*; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000378:metabolism; D008156:Luciferases; D011493:Protein Kinase C / Q000378:metabolism; D000091283:Protein Kinase D2; D011494:Protein Kinases / Q000378:metabolism*; D034622:RNA Interference; D020871:RNA Stability / Q000187:drug effects / Q000502:physiology*; D060888:Real-Time Polymerase Chain Reaction; D051880:Receptors, Notch / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology
chemical_list: C486398:BCL6B protein, human; D018841:HSP90 Heat-Shock Proteins; C493165:HSP90AB1 protein, human; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D000091283:Protein Kinase D2; C497570:RBPJ protein, human; D051880:Receptors, Notch; D012097:Repressor Proteins; D042461:Vascular Endothelial Growth Factor A; D008156:Luciferases; D011494:Protein Kinases; C089212:protein kinase D; D011493:Protein Kinase C