| Abstract: |
Nucleocytoplasmic shuttling of class IIa of histone deacetylases (HDACs) is a key mechanism that controls cell fate and animal development. We have identified the filamin B (FLNB) as a novel HDAC7-interacting protein that is required for temporal and spatial regulation of vascular endothelial growth factor (VEGF)-mediated HDAC7 cytoplasmic sequestration. This interaction occurs in the cytoplasm and requires monoubiquitination of an evolutionarily conserved lysine 1147 (K1147) in the immunoglobulin (Ig)-like repeat 10 (R10) of FLNB and the nuclear localization sequence of HDAC7. Inhibition of protein kinase C (PKC) blocks VEGF-induced ubiquitination of FLNB and its interaction with HDAC7. Small interfering RNA (siRNA) knockdown of FLNB or ubiquitin (Ub) in human primary endothelial cells blocks VEGF-mediated cytoplasmic accumulation of HDAC7, reduces VEGF-induced expression of the HDAC7 target genes Mmp-10 and Nur77, and inhibits VEGF-induced vascular permeability. Using dominant negative mutants and rescue ex periments, we demonstrate the functional significance of FLNB K1147 to interfere with the ability of phorbol myristate acetate (PMA) to promote FLNB-mediated cytoplasmic accumulation of HDAC7. Taken together, our data show that VEGF and PKC promote degradation-independent protein ubiquitination of FLNB to control intracellular trafficking of HDAC7. © 2013, American Society for Microbiology. |
| Keywords: |
vasculotropin; controlled study; protein expression; unclassified drug; human cell; ubiquitin; protein analysis; protein degradation; small interfering rna; rna, small interfering; rna interference; protein interaction; cell line, tumor; hela cells; microfilament proteins; animalia; endothelium cell; endothelial cells; ubiquitination; amino acid sequence; protein transport; cell migration; cell movement; cytoplasm; protein structure, tertiary; protein kinase c; indoles; neovascularization, physiologic; nuclear localization signal; histone deacetylases; cell membrane permeability; carbazoles; phorbol 13 acetate 12 myristate; tetradecanoylphorbol acetate; maleimides; nuclear receptor nur77; nuclear receptor subfamily 4, group a, member 1; histone deacetylase 7; vascular endothelial growth factors; lysine derivative; contractile proteins; filamin; protein filamin b; stromelysin 2; matrix metalloproteinase 10
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