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Blood, 1 May 2008, Vol. 111, No. 9, pp. 4617-4626.
Prepublished online as a Blood First Edition Paper on February 21, 2008; DOI 10.1182/blood-2007-10-121137.
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IMMUNOBIOLOGY
Proteasome-dependent autoregulation of Bruton tyrosine kinase (Btk) promoter via NF- B
Liang Yu1,
Abdalla J. Mohamed1,
Oscar E. Simonson1,
Leonardo Vargas1,
K. Emelie M. Blomberg1,
Bo Björkstrand2,
H. Jose Arteaga1,3,
Beston F. Nore1, and
C. I. Edvard Smith1
1 Department of Laboratory Medicine, Clinical Research Center and
2 Division of Hematology, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden; and
3 School of Medicine, Universidad Industrial de Santander, Bucaramanga, Colombia
Bruton tyrosine kinase (Btk) is critical for B-cell development. Btk regulates a plethora of signaling proteins, among them nuclear factor-[ ]B (NF-B). Activation of NF-B is a hallmark of B cells, and NF-B signaling is severely compromised in Btk deficiency. We here present strong evidence indicating that NF-B is required for efficient transcription of the Btk gene. First, we found that proteasome blockers and inhibitors of NF-B 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-B–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-B signaling), as well as NF-B binding sequence-oligonucleotide decoys block Btk transcription. We also demonstrate that Btk induces NF-B activity in mice. Collectively, we show that Btk uses a positive autoregulatory feedback mechanism to stimulate transcription from its own promoter via NF-B.
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gkn413v1.
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