title: c-Jun triggers apoptosis in human vascular endothelial cells.
abstract: In endothelial cells (ECs), the transcription factor c-Jun is induced by a variety of stimuli that perturb EC function. To extend our understanding of the role of c-Jun in EC physiology, we have directed overexpression of c-Jun in human umbilical vein ECs by using a tetracycline-regulated adenoviral expression system. In this study, we report a novel observation using this system. Specific expression of c-Jun is a sufficient trigger for ECs to undergo apoptosis, as demonstrated by a set of combined assays including an ELISA specific for histone-associated DNA fragmentation, DNA laddering, and TdT-mediated dUTP nick end labeling (TUNEL). Tetracycline can effectively shut off c-Jun overexpression and prevent EC apoptosis. Cleavage of poly(ADP-ribose) polymerase was also detected in ECs overexpressing c-Jun. Moreover, inhibitors of cysteine proteases blocked the apoptosis, suggesting a caspase-associated mechanism involved in proapoptotic effects of c-Jun. To gain further insight into the role of c-Jun as a pathophysiological regulator of EC death, TAM67, a dominant-negative mutant of c-Jun, was overexpressed in human umbilical vein ECs to abrogate endogenous c-Jun/activator protein-1 activation. H(2)O(2)-triggered apoptosis was largely attenuated in ECs overexpressing TAM67. Together, these results suggest that c-Jun, as a proapoptotic molecule, may play a role in mediating the cell death program in vascular endothelium.
authors.affiliation: Division of Biomedical Sciences, University of California, Riverside 92521, USA. nanping.wang@ucr.edu
authors.forename: N
authors.initials: N
authors.lastname: Wang
authors.forename: L
authors.initials: L
authors.lastname: Verna
authors.forename: S
authors.initials: S
authors.lastname: Hardy
authors.forename: Y
authors.initials: Y
authors.lastname: Zhu
authors.forename: K S
authors.initials: KS
authors.lastname: Ma
authors.forename: M J
authors.initials: MJ
authors.lastname: Birrer
authors.forename: M B
authors.initials: MB
authors.lastname: Stemerman
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000502:physiology; D002478:Cells, Cultured; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D003587:Cytomegalovirus / Q000235:genetics; D004730:Endothelium, Vascular / Q000166:cytology*; D004789:Enzyme Activation; D005786:Gene Expression Regulation / Q000187:drug effects; D016758:Genes, jun; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D016755:Proto-Oncogene Proteins c-jun / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000502:physiology; D013752:Tetracycline / Q000494:pharmacology; D015533:Transcriptional Activation; D014162:Transfection; D014471:Umbilical Veins
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D009842:Oligopeptides; D016755:Proto-Oncogene Proteins c-jun; D011993:Recombinant Fusion Proteins; C110772:benzoylcarbonyl-aspartyl-glutamyl-valyl-aspartyl-fluoromethyl ketone; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D006861:Hydrogen Peroxide; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D013752:Tetracycline