IngentaConnect NF-B regulates the transcription of protein tyrosine kinase Tec

Authors: Yu, Liang; Simonson, Oscar E.¹; Mohamed, Abdalla J.¹; Smith, C. I. Edvard¹

Source: FEBS Journal, Volume 276, Number 22, November 2009 , pp. 6714-6724(11)

Abstract:

The tyrosine kinase expressed in hepatocellular carcinoma (Tec) is a non-receptor protein tyrosine kinase (PTK) that is expressed in hematopoietic cells, such as B and T lymphocytes, myeloid lineage cells and neutrophils. Mutations in the human Btk gene cause X-linked agammaglobulinemia (XLA), but the corresponding mutation in mice results in a much milder defect. However, the combined inactivation of Btk and Tec genes in mice cause a severe phenotype resembling XLA. Tec is involved in the regulation of both B and T lymphocytes, fine-tuning of TCR/BCR signaling, and also activation of the nuclear factor of activated T cells. Previous work has shown that the transcription factors Sp1 and PU.1 can bind and regulate the Tec promoter. In this study, we demonstrate that NF-κB is an essential transcription factor for optimal expression of the Tec gene, and identify a unique functionally active NF-κB binding site in its promoter. The NF-κB subunit p65/RelA directly induced transcriptional activity of the Tec promoter. Moreover, we also found that proteasome inhibitors, including Bortezomib, repress Tec transcription through inactivation of the NF-κB signaling pathway. This study, together with our previous findings on the transcriptional regulation of Btk (Bruton's tyrosine kinase) by proteasome inhibitors, provides important insight into the molecular mechanism(s) underlying the role of NF-κB in Tec family kinase signaling and lymphocyte development.

Keywords: Bortezomib; hydrodynamic transfection; NF-κB; Tec; transcription

Document Type: Research article

DOI: 10.1111/j.1742-4658.2009.07385.x

Affiliations: 1: Department of Laboratory Medicine, Clinical Research Center, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden

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NF-κB regulates the transcription of protein tyrosine kinase Tec