title: Role of A20 in cIAP-2 protection against tumor necrosis factor α (TNF-α)-mediated apoptosis in endothelial cells.
abstract: Tumor necrosis factor α (TNF-α) influences endothelial cell viability by altering the regulatory molecules involved in induction or suppression of apoptosis. However, the underlying mechanisms are still not completely understood. In this study, we demonstrated that A20 (also known as TNFAIP3, tumor necrosis factor α-induced protein 3, and an anti-apoptotic protein) regulates the inhibitor of apoptosis protein-2 (cIAP-2) expression upon TNF-α induction in endothelial cells. Inhibition of A20 expression by its siRNA resulted in attenuating expression of TNF-α-induced cIAP-2, yet not cIAP-1 or XIAP. A20-induced cIAP-2 expression can be blocked by the inhibition of phosphatidyl inositol-3 kinase (PI3-K), but not nuclear factor (NF)-κB, while concomitantly increasing the number of endothelial apoptotic cells and caspase 3 activation. Moreover, TNF-α-mediated induction of apoptosis was enhanced by A20 inhibition, which could be rescued by cIAP-2. Taken together, these results identify A20 as a cytoprotective factor involved in cIAP-2 inhibitory pathway of TNF-α-induced apoptosis. This is consistent with the idea that endothelial cell viability is dependent on interactions between inducers and suppressors of apoptosis, susceptible to modulation by TNF-α.
authors.affiliation: School of Preclinical Medicine, Beijing University of Chinese Medicine, Beijing 100029, China. guoshz@bucm.edu.cn.
authors.forename: Shuzhen
authors.initials: S
authors.lastname: Guo
authors.affiliation: CardioVascular Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA. angela.messmerblust@gmail.com.
authors.forename: Angela F
authors.initials: AF
authors.lastname: Messmer-Blust
authors.affiliation: CardioVascular Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA. wujiaping@hotmail.com.
authors.forename: Jiaping
authors.initials: J
authors.lastname: Wu
authors.affiliation: CardioVascular Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA. xsong103@gmail.com.
authors.forename: Xiaoxiao
authors.initials: X
authors.lastname: Song
authors.affiliation: CardioVascular Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA. mphilbric@gmail.com.
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Philbrick
authors.affiliation: CardioVascular Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA. shiejuelon66@yahoo.com.
authors.forename: Jue-Lon
authors.initials: JL
authors.lastname: Shie
authors.affiliation: CardioVascular Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA. jamalrana@gmail.com.
authors.forename: Jamal S
authors.initials: JS
authors.lastname: Rana
authors.affiliation: CardioVascular Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA. jianliboston@gmail.com.
authors.forename: Jian
authors.initials: J
authors.lastname: Li
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D002417:Cattle; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D009025:Morpholines / Q000494:pharmacology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D044767:Ubiquitin-Protein Ligases
chemical_list: D002867:Chromones; D004268:DNA-Binding Proteins; D051034:Inhibitor of Apoptosis Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009025:Morpholines; D009687:Nuclear Proteins; D000081082:Phosphoinositide-3 Kinase Inhibitors; D014409:Tumor Necrosis Factor-alpha; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C494832:BIRC3 protein, human; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D044767:Ubiquitin-Protein Ligases; D058539:Phosphatidylinositol 3-Kinase; C076529:TNFAIP3 protein, human; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D053148:Caspase 3