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The C-terminal domain of A1/Bfl-1 regulates its anti-inflammatory function in human endothelial cells.

Authors
  • Guedes, Renata P1
  • Rocha, Eduardo
  • Mahiou, Jerome
  • Moll, Herwig P
  • Arvelo, Maria B
  • Taube, Janis M
  • Peterson, Clayton R
  • Kaczmarek, Elzbieta
  • Longo, Christopher R
  • da Silva, Cleide G
  • Ferran, Christiane
  • 1 Department of Surgery, Harvard Medical School, Boston, MA 02215, USA.
Type
Published Article
Journal
Biochimica et Biophysica Acta
Publisher
Elsevier
Publication Date
Jun 01, 2013
Volume
1833
Issue
6
Pages
1553–1561
Identifiers
DOI: 10.1016/j.bbamcr.2013.03.001
PMID: 23499873
Source
Medline
Language
English
License
Unknown

Abstract

A1/Bfl-1 is a NF-κB dependent, anti-apoptotic Bcl-2 family member that contains four Bcl-2 homology domains (BH) and an amphipathic C-terminal domain, and is expressed in endothelial cells (EC). Based on NF-κB reporter assays in bovine aortic EC, we have previously demonstrated that A1, like Bcl-2 and Bcl-xL, inhibits NF-κB activation. These results, however, do not fully translate when evaluating the cell's own NF-κB machinery in human EC overexpressing A1 by means of recombinant adenovirus (rAd.) mediated gene transfer. Indeed, overexpression of full-length A1 in human umbilical vein EC (HUVEC), and human dermal microvascular EC (HDMEC) failed to inhibit NF-κB activation. However, overexpression of a mutant lacking the C-terminal domain of A1 (A1ΔC) demonstrated a potent NF-κB inhibitory effect in these cells. Disparate effects of A1 and A1ΔC on NF-κB inhibition in human EC correlated with mitochondrial (A1) versus non-mitochondrial (A1ΔC) localization. In contrast, both full-length A1 and A1ΔC protected EC from staurosporine (STS)-induced cell death, indicating that mitochondrial localization was not necessary for A1's cytoprotective function in human EC. In conclusion, our data uncover a regulatory role for the C-terminal domain of A1 in human EC: anchoring A1 to the mitochondrion, which conserves but is not necessary for its cytoprotective function, or by its absence freeing A1 from the mitochondrion and uncovering an additional anti-inflammatory effect. Copyright © 2013 Elsevier B.V. All rights reserved.

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