NF-kappaB regulates the transcription of protein tyrosine kinase Tec.
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-kappaB is an essential transcription factor for optimal expression of the Tec gene, and identify a unique functionally active NF-kappaB binding site in its promoter. The NF-kappaB 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-kappaB 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-kappaB in Tec family kinase signaling and lymphocyte development.
Yu
Liang
L
Department of Laboratory Medicine, Clinical Research Center, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden. liang.yu@ki.se
Simonson
Oscar E
OE
Mohamed
Abdalla J
AJ
Smith
C I Edvard
CI
D000818:Animals; D001665:Binding Sites / Q000235:genetics; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D019295:Computational Biology; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D051379:Mice; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000235:genetics; D011505:Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism*
D016328:NF-kappa B; C089848:Tec protein-tyrosine kinase; D011505:Protein-Tyrosine Kinases