Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.1.21 (thymidine kinase)
 7,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Two species, Fc epsilon RIIa and Fc epsilon RIIb, of the human low-affinity receptor for IgE (Fc epsilon RII/CD23) have recently been described. They differ by only six amino acids in the cytoplasmic N-terminus and are generated by different cell-specific transcriptional start sites that lead to distinct 5'-leader sequences in the corresponding mRNA. In this study, we present the analysis of the promoter which is regulating the expression of the B cell-specific Fc epsilon RIIa. Our data show that this promoter is flanked by several long repetitive elements that are influencing transcription in the Burkitt lymphoma B cell line Jijoye. Serial deletions of the 5'-flanking region of the promoter revealed two major regulatory segments that have either inhibitory or enhancing effects on transcription. In addition, IL-4 caused a two- to four-fold up-regulation of the Fc epsilon RIIa promoter activity and the DNA element responsible was mapped within the first 250 bp of the 5'-flanking region. These results were confirmed by transferring the DNA segment containing the putative IL-4 responsive element to a heterologous thymidine kinase promoter. It was concluded that IL-4 augments the Fc epsilon RIIa expression by transcriptional regulation.
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PMID:Expression of human lymphocyte IgE receptor (Fc epsilon RII/CD23). Identification of the Fc epsilon RIIa promoter and its functional analysis in B lymphocytes. 253 Feb 83

The activation of germ-line promoters in the Ig heavy chain loci is regulated by cytokines as part of the regulation of B cell commitment to production of new antibody isotypes. Activation of the germ-line promoter of the epsilon heavy chain locus (Gepsilon) and production of IgE are induced by IL-4 and each is virtually undetectable in the absence of IL-4 or the homologous cytokine IL-13. Basal expression of the Gepsilon promoter is repressed by the non-histone chromosomal protein HMG-I(Y), which also contributes to promoter inducibility, and IL-4 stimulates phosphorylation of the C-terminus of HMG-I(Y) through a rapamycin-sensitive pathway. IL-4 treatment of mouse B cells also induces a Gepsilon DNA binding activity with the properties of IL-4 NAF, which is rapidly induced and requires phosphotyrosine for DNA binding activity. This protein binds to a different site from HMG-I(Y), but the IL-4 NAF/NF-IL-4 binding site also is a negative element more active in repression of basal transcription of the Gepsilon promoter. This site acts as a negative element when transferred to the thymidine kinase promoter, but does not confer inducibility. In contrast to HMG-I(Y), IL-4 NAF/NF-IL-4 activation is refractory to rapamycin but sensitive to genistein. These findings indicate that two independent signal transduction pathways diverge from the IL-4 receptor and suggest that normal expression of Gepsilon RNA or IgE is low in part because the germ-line promoter is kept in a state of repression which requires de-repression through several cooperative pathways. These pathways target conserved nucleotide sequence motifs whose precise function depends on the promoter context in which they are situated.
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PMID:Independent pathways for de-repression of the mouse Ig heavy chain germ-line epsilon promoter: an IL-4 NAF/NF-IL-4 site as a context-dependent negative element. 875 43

Asthma is characterized by chronic eosinophilic inflammation of the airways, and allergen-specific Th2 lymphocytes are thought to play a major role in the development and maintenance of this type of inflammation in allergic asthma. It is generally accepted that airway dendritic cells (DC) are essential for stimulating naive T cells in a primary immune response to inhaled Ag and for the development of allergic sensitization. We have examined the role of airway DC in stimulating memory T cells in a secondary response to inhaled Ag and the subsequent development of chronic airway inflammation. In our mouse model of asthma, OVA aerosol challenge in OVA-sensitized mice leads to CD4-dependent peribronchial and perivascular eosinophilic inflammation, lung Th2 cytokine production, and systemic IgE production. We have used conditional depletion of airway DC by treatment of thymidine kinase-transgenic mice with the antiviral drug ganciclovir to deplete DC during the secondary exposure to OVA. In sensitized thymidine kinase-transgenic mice, a significant decrease in the number of bronchoalveolar CD4 and CD8 T lymphocytes and B lymphocytes was seen after ganciclovir treatment. In addition, Th2 cytokine-associated eosinophilic airway inflammation was almost completely suppressed. These studies demonstrate for the first time that the DC is essential for presenting inhaled Ag to previously primed Th2 cells in the lung, leading to chronic eosinophilic airway inflammation. Altering the function of airway DC may therefore be an important target for new anti-asthma therapy.
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PMID:Dendritic cells are required for the development of chronic eosinophilic airway inflammation in response to inhaled antigen in sensitized mice. 955 20