Histone deacetylase 7 controls endothelial cell growth through modulation of beta-catenin.
RATIONALE: Histone deacetylase (HDAC)7 is expressed in the early stages of embryonic development and may play a role in endothelial function. OBJECTIVE: This study aimed to investigate the role of HDAC7 in endothelial cell (EC) proliferation and growth and the underlying mechanism. METHODS AND RESULTS: Overexpression of HDAC7 by adenoviral ... gene transfer suppressed human umbilical vein endothelial cell (HUVEC) proliferation by preventing nuclear translocation of beta-catenin and downregulation of T-cell factor-1/Id2 (inhibitor of DNA binding 2) and cyclin D1, leading to G(1) phase elongation. Further assays with the TOPFLASH reporter and quantitative RT-PCR for other beta-catenin target genes such as Axin2 confirmed that overexpression of HDAC7 decreased beta-catenin activity. Knockdown of HDAC7 by lentiviral short hairpin RNA transfer induced beta-catenin nuclear translocation but downregulated cyclin D1, cyclin E1 and E2F2, causing HUVEC hypertrophy. Immunoprecipitation assay and mass spectrometry analysis revealed that HDAC7 directly binds to beta-catenin and forms a complex with 14-3-3 epsilon, zeta, and eta proteins. Vascular endothelial growth factor treatment induced HDAC7 degradation via PLCgamma-IP3K (phospholipase Cgamma-inositol-1,4,5-trisphosphate kinase) signal pathway and partially rescued HDAC7-mediated suppression of proliferation. Moreover, vascular endothelial growth factor stimulation suppressed the binding of HDAC7 with beta-catenin, disrupting the complex and releasing beta-catenin to translocate into the nucleus. CONCLUSIONS: These findings demonstrate that HDAC7 interacts with beta-catenin keeping ECs in a low proliferation stage and provides a novel insight into the mechanism of HDAC7-mediated signal pathways leading to endothelial growth.
Mesh Terms:
14-3-3 Proteins, Active Transport, Cell Nucleus, Adenoviridae, Cell Cycle, Cell Proliferation, Cells, Cultured, Cyclin D1, Cyclin E, E2F2 Transcription Factor, Endothelial Cells, Genetic Vectors, Histone Deacetylases, Humans, Hypertrophy, Immunoprecipitation, Inhibitor of Differentiation Protein 2, Mass Spectrometry, Neovascularization, Physiologic, Oncogene Proteins, Phospholipase C gamma, Phosphotransferases (Alcohol Group Acceptor), Protein Binding, Protein Processing, Post-Translational, RNA Interference, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, Time Factors, Transduction, Genetic, Vascular Endothelial Growth Factor A, beta Catenin
14-3-3 Proteins, Active Transport, Cell Nucleus, Adenoviridae, Cell Cycle, Cell Proliferation, Cells, Cultured, Cyclin D1, Cyclin E, E2F2 Transcription Factor, Endothelial Cells, Genetic Vectors, Histone Deacetylases, Humans, Hypertrophy, Immunoprecipitation, Inhibitor of Differentiation Protein 2, Mass Spectrometry, Neovascularization, Physiologic, Oncogene Proteins, Phospholipase C gamma, Phosphotransferases (Alcohol Group Acceptor), Protein Binding, Protein Processing, Post-Translational, RNA Interference, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, Time Factors, Transduction, Genetic, Vascular Endothelial Growth Factor A, beta Catenin
Circ. Res.
Date: Apr. 16, 2010
PubMed ID: 20224040
View in: Pubmed Google Scholar
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