title: Proteasome inhibitors enhance endothelial thrombomodulin expression via induction of Krüppel-like transcription factors.
abstract: OBJECTIVE
  Impairment of the thrombomodulin-protein C anticoagulant pathway has been implicated in pathological thrombosis associated with malignancy. Patients who receive proteasome inhibitors as part of their chemotherapeutic regimen appear to be at decreased risk for thromboembolic events. We investigated the effects of proteasome inhibitors on endothelial thrombomodulin expression and function.
  
  
  RESULTS
  Proteasome inhibitors as a class markedly induced the expression of thrombomodulin and enhanced the protein C activating capacity of endothelial cells. Thrombomodulin upregulation was independent of NF-kappaB signaling, a principal target of proteasome inhibitors, but was instead a direct consequence of increased expression of the Krüppel-like transcription factors, KLF2 and KLF4. These effects were confirmed in vivo, where systemic administration of a proteasome inhibitor enhanced thrombomodulin expression that was paralleled by changes in the expression of KLF2 and KLF4.
  
  
  CONCLUSIONS
  These findings identify a novel mechanism of action of proteasome inhibitors that may help to explain their clinically observed thromboprotective effects.
authors: Department of Medicine, Johns Hopkins School of Medicine, Ross 1165, 720 Rutland Avenue, Baltimore, MD 21205, USA.
authors: Toyoko
authors: T
authors: Hiroi
authors: Clayton B
authors: CB
authors: Deming
authors: Haige
authors: H
authors: Zhao
authors: Baranda S
authors: BS
authors: Hansen
authors: Elisabeth K
authors: EK
authors: Arkenbout
authors: Thomas J
authors: TJ
authors: Myers
authors: Michael A
authors: MA
authors: McDevitt
authors: Jeffrey J
authors: JJ
authors: Rade
mesh_terms: D000818:Animals; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D011480:Protease Inhibitors / Q000494:pharmacology*; D061988:Proteasome Inhibitors; D011486:Protein C / Q000502:physiology; D011719:Pyrazines / Q000494:pharmacology*; D018180:Thrombomodulin / Q000235:genetics* / Q000502:physiology
chemical_list: D001897:Boronic Acids; C096161:KLF2 protein, human; C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D016328:NF-kappa B; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D011486:Protein C; D011719:Pyrazines; D018180:Thrombomodulin; D000069286:Bortezomib