title: Thioredoxin-interacting protein mediates nuclear-to-plasma membrane communication: role in vascular endothelial growth factor 2 signaling.
abstract: OBJECTIVE
  Thioredoxin-interacting protein (TXNIP) and poly-ADP-ribose polymerase 1 (PARP1) are both regulated by changes in cellular reduction-oxidation (redox) state and localize to the nucleus basally in human umbilical vein endothelial cells (HUVEC). Previously we showed a novel mechanism for PARP1 inhibition-mediated HUVEC survival through activation of vascular endothelial growth factor receptor 2 (VEGFR2) signaling in response to stress-induced apoptosis. In addition, we showed TXNIP translocation to the plasma membrane (PM) and activation of VEGFR2 in response to physiological stimuli. Because TXNIP is an α-arrestin that regulates VEGFR2 signaling, we hypothesized that PARP1 regulates TXNIP localization and function that might affect HUVEC stress-induced apoptosis.
  
  
  RESULTS
  HUVEC treated with 10 μmol/L PARP1 inhibitor (PJ34) were protected from TNF (10 ng/mL) or H(2)O(2) (300 μmol/L) mediated cell death. HUVEC transfected with TXNIP siRNA lost the protective effect of PARP1 inhibition, suggesting a protective role for TXNIP. Using immunofluorescence, cell fractionation analysis, and plasma membrane sheet assay, TXNIP was shown to translocate to the plasma membrane after PARP1 inhibition. TXNIP translocation was associated with activation of VEGFR2 signaling. Functionally, TXNIP-PARP1 interaction was decreased on PJ34 treatment, suggesting PARP1 as a novel regulator of TXNIP localization and function.
  
  
  CONCLUSIONS
  These findings demonstrate a novel regulatory mechanism of TXNIP by PARP1 to mediate activation of plasma membrane signaling and cell survival.
authors.affiliation: Department of Medicine, University of Rochester School of Medicine and Dentistry, Aab Cardiovascular Research Institute, Rochester, NY 14642, USA.
authors.forename: Oded N
authors.initials: ON
authors.lastname: Spindel
authors.forename: Chen
authors.initials: C
authors.lastname: Yan
authors.forename: Bradford C
authors.initials: BC
authors.lastname: Berk
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002450:Cell Communication / Q000502:physiology*; D002462:Cell Membrane / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018919:Neovascularization, Physiologic / Q000502:physiology*; D015398:Signal Transduction; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*
chemical_list: D040301:Vascular Endothelial Growth Factor Receptor-2