title: Proteasome-dependent autoregulation of Bruton tyrosine kinase (Btk) promoter via NF-kappaB.
abstract: Bruton tyrosine kinase (Btk) is critical for B-cell development. Btk regulates a plethora of signaling proteins, among them nuclear factor-[kappa]B (NF-kappaB). Activation of NF-kappaB is a hallmark of B cells, and NF-kappaB signaling is severely compromised in Btk deficiency. We here present strong evidence indicating that NF-kappaB is required for efficient transcription of the Btk gene. First, we found that proteasome blockers and inhibitors of NF-kappaB signaling suppress Btk transcription and intracellular expression. Similar to Btk, proteasome inhibitors also reduced the expression of other members of this family of kinases, Itk, Bmx, and Tec. Second, 2 functional NF-kappaB-binding sites were found in the Btk promoter. Moreover, in live mice, by hydrodynamic transfection, we show that bortezomib (a blocker of proteasomes and NF-kappaB signaling), as well as NF-kappaB binding sequence-oligonucleotide decoys block Btk transcription. We also demonstrate that Btk induces NF-kappaB activity in mice. Collectively, we show that Btk uses a positive autoregulatory feedback mechanism to stimulate transcription from its own promoter via NF-kappaB.
authors.affiliation: Department of Laboratory Medicine, Clinical Research Center, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden. liang.yu@ki.se
authors.forename: Liang
authors.initials: L
authors.lastname: Yu
authors.forename: Abdalla J
authors.initials: AJ
authors.lastname: Mohamed
authors.forename: Oscar E
authors.initials: OE
authors.lastname: Simonson
authors.forename: Leonardo
authors.initials: L
authors.lastname: Vargas
authors.forename: K Emelie M
authors.initials: KE
authors.lastname: Blomberg
authors.forename: Bo
authors.initials: B
authors.lastname: Björkstrand
authors.forename: H Jose
authors.initials: HJ
authors.lastname: Arteaga
authors.forename: Beston F
authors.initials: BF
authors.lastname: Nore
authors.forename: C I Edvard
authors.initials: CI
authors.lastname: Smith
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D001665:Binding Sites; D025461:Feedback, Physiological; D006706:Homeostasis; D051379:Mice; D016328:NF-kappa B / Q000502:physiology*; D011401:Promoter Regions, Genetic; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D014158:Transcription, Genetic
chemical_list: D016328:NF-kappa B; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625951:Btk protein, mouse; D046988:Proteasome Endopeptidase Complex