Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.2 (focal adhesion kinase)
44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The expression of the junB gene parallels the expression of the MHC class I genes in Adenovirus (Ad) transformed cells. In Ad12E1-transformed primary BRK cells both genes are transcriptionally repressed only when the 13S product of Ad12E1A is present. This indicates that repression of MHC class I and junB genes is a function of conserved region 3 (CR3) of the Ad12E1A protein. In Ad5-transformed BRK cells expression of these genes is unchanged. In established NRK cells, however, introduction of Ad12E1A does not cause repression of the MHC class I and junB genes, but in these cells Ad5E1A increases the expression of both MHC class I and junB. Using mutant Ad5E1A genes, it is shown that this activation is mediated by CR1. Introduction of a functional junB gene under the control of a heterologous promoter in Ad12E1-transformed BRK cells causes no increase in MHC class I expression. This demonstrates that the down-regulation of junB is not directly responsible for class I repression, but rather that both genes are coregulated by the Ad12E1 region.
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PMID:Co-regulated expression of junB and MHC class I genes in adenovirus-transformed cells. 190 58

The thymic stromal network is complex and heterogeneous, containing thymic epithelial cells which are thought to play an important role during T-cell development and thymic fibroblasts which role is less defined. We herein present a phenotypic and functional comparison between defined thymic stromal cell populations. We transfected SV40 ori- into fetal and postnatal thymic stromal cell cultures and obtained SV40-immortalized clones of epithelial and fibroblastic nature as demonstrated by expression of intracellular keratin. These various clones were characterized in detail and compared to their untransfected bulk culture counterparts for phenotype, cytokine gene expression and cytokine production. All the different thymic stromal cells examined, constitutively expressed ICAM-1, LFA-3, MHC class I antigens, CD44, and the genes coding for IL-7, SCF and TGF-beta, but not TNF-alpha. After IL-1 stimulation, epithelial cells seemed to produce more GM-CSF than fibroblasts, and that trend was also seen for IL-6 secretion. SV40 cells were also regulated by IFN-gamma which induced MHC class II antigens and inhibited the IL-1 induced GM-CSF production. SV40 cells differed from their untransfected counterparts by an atypical expression of CD40 and lacked constitutive IL-1 alpha gene expression. We isolated clones with distinct properties, 24SV48, a highly proliferative CD34 positive TEC secreting low levels of GM-CSF and lacking constitutive IL-1 alpha and beta gene expression, and CT1SV93, an epithelial clone of postnatal origin with a high IL-1-induced cytokine production. In spite of differences with untransfected bulk cultures, the various SV40 immortalized clones may represent useful tools to further study the human thymic stroma.
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PMID:Untransfected and SV40-transfected fetal and postnatal human thymic stromal cells. Analysis of phenotype, cytokine gene expression and cytokine production. 750 57

Thymic epithelial and nurse cells (TEC/TNC) synthesize an oxytocin (OT)-like peptide in association with a neurophysin (NP)-related protein in a way similar to in the hypothalamo-neurohypophysial (NHP) system. The central T-cell tolerance of the NHP neuroendocrine functions have been proposed to be mediated through these thymic NHP-related peptides due to their close homology with the NHP neurohormones OT and vasopressin (VP). In order to investigate their putative presentation by proteins of the major histocompatibility complex (MHC), human thymic membranes were purified and passed through an immunoaffinity column using mAb B9.12 directed to the monomorphic determinant of human MHC class I proteins. This methodology provided the following observations: (1) a NP-like protein is translocated in human thymic membranes and is retained by B9.12 on the column; (2) the MW of this NP-like material (50-55 kD) is quite different from the MW of hypothalamic NP proteins (10 kD), and (3) this thymic NP-like protein could be identified on Western blots with mAb B9.12. The precise extent of this relationship between the thymic NP-like protein and the Ig/MHC superfamily is actually investigated through the characterization of the genetic mechanisms responsible for the thymic expression of NHP-related peptides. Given the physiological importance of OT and of its binding to NP for transport along the axonal processes of the NHP tract, we postulate that, somewhat analogously, the thymic NP-/MHC class I-related protein could be involved in the presentation of the OT-like peptide to immature T-cells.
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PMID:Membrane translocation and relationship with MHC class I of a human thymic neurophysin-like protein. 830 78

The role of the medullary thymic epithelial cells in tolerance induction to MHC class I restricted self peptides has been analyzed by studying the beta-galactosidase (beta-gal)-specific cytotoxic T cell response of a transgenic mouse expressing beta-gal in the thymus, skin, and central nervous system (Tg beta-gal mouse). Our results showed that: 1) beta-gal expression in the thymus was limited in a subpopulation of medullary epithelial cells, and bone marrow-derived thymic cells were beta-gal-1; 2) Tg beta-gal mice did not mount an anti-beta-gal CTL response even in the presence of exogenous IL-2, while Tg beta-gal-->B6 chimeras responded to beta-gal as strongly as NTg beta-gal mice; 3) Tg beta-gal mice did not generate CTL against the immunodominant Kb-restricted beta-gal 497-504 peptide; 4) tolerance was due to the thymic epithelial cells that expressed beta-gal because nude mice grafted with thymus from Tg beta-gal mice were also unable to respond to beta-gal; 5) the Tg beta-gal mouse-derived beta-gal+ medullary epithelial TEC.X10 line presented the Kb-restricted beta-gal 497-504 epitope. In conclusion, these results demonstrate that medullary thymic epithelial cells induce a complete tolerance towards class I-restricted self peptides presented on their own surface.
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PMID:Medullary thymic epithelial cells induce tolerance to intracellular proteins. 855 24

In the present study, we investigated the developmental potential of purified populations of transitional CD4inCD8hi and CD4hiCD8in thymocytes that were further defined according to their differentiation stage by their levels of T cell receptor (TCR) expression into TCRlo, TCRin and TCRhi subpopulations. The differentiation potential of each of these subsets was tested in vitro in a single-cell suspension culture assay that showed that CD4inCD8hiTCRhi are precursors of CD8 single-positive cells, whereas CD4hiCD8inTCRin/hi are precursors of both CD4 and CD8 single-positive thymocytes. The analysis of transitional subsets in mutant mice for either beta 2-microglobulin or major histocompatibility complex (MHC) class II further revealed that lineage commitment to the CD8 lineage requires a TCR-MHC class I engagement, presumably at the immature double-positive stage of thymic development, while CD4 commitment does not require an MHC class II-mediated signal, but rather occurs by default. Using the addition of MHC class I- or class II-expressing cells or the addition of total thymocytes to purified sorted transitional precursors for the duration of the cultures in vitro, we identified an additional stage of differentiation for both CD4 and CD8 lineages that requires a positive selection signal. Examination of protein tyrosine phosphorylation of transitional precursors revealed that CD4inCD8hi transitional cells contain a high level of a 70-kDa phosphorylated protein consistent with a role for ZAP70 in the signal transduction during the positive selection of CD8+ cells.
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PMID:CD8/CD4 lineage commitment occurs by an instructional/default process followed by positive selection. 861 19

Cross-linking of MHC class I (MHC-I) molecules on human T cells induces signal-transduction events, including activation of tyrosine kinases, tyrosine phosphorylation of phospholipase C-gamma 1, and elevation of the intracellular free calcium concentration. In this study, we demonstrate that the ZAP70 tyrosine kinase is tyrosine phosphorylated in Jurkat T cells and in purified peripheral T cells after MHC-I ligation. The tyrosine-phosphorylated ZAP70 kinase exhibits a particular phenotype with low affinities for proteins at 21, 40, 60, and 120 kDa, proteins normally co-precipitated with ZAP70 after TCR/CD3 stimulation. The phosphorylation of ZAP70 after MHC-I ligation was dependent on TCR/CD3 surface expression. One of the natural substrates for ZAP70 is the zeta-chain dimer of the TCR/CD3 complex. MHC-I cross-linking induces a phosphorylated zeta-protein that migrates as a dimer at 42 kDa in SDS-PAGE and differs from the 38-kDa phosphorylated zeta-protein dimer induced by TCR/CD3 cross-linking. Furthermore, we demonstrate that the p56lck tyrosine kinase is tyrosine phosphorylated following MHC-I ligation, and that a p56lck-negative Jurkat T cell mutant does not induce phosphorylation of the zeta-chain and the ZAP70 kinase following MHC-I ligation. Previous studies have demonstrated that lack or diminished activation of ZAP70 is involved in the induction of anergy or apoptosis in T cells. Likewise, MHC-I cross-linking of Jurkat T cells results in growth arrest and induction of apoptosis that is strongly inhibited by herbimycin A, suggesting an essential role of tyrosine kinase activity in the process leading to apoptosis.
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PMID:MHC class I ligation of human T cells activates the ZAP70 and p56lck tyrosine kinases, leads to an alternative phenotype of the TCR/CD3 zeta-chain, and induces apoptosis. 912 Feb 73

The proteasome contributes to the generation of most of the peptide ligands of MHC class I molecules. To compare the identity of the peptides generated by the proteasome with those finally presented by MHC class I molecules, we generated a monoclonal antibody recognizing the C-terminal part of the dominant H2-Kd ligand SYFPEITHI derived from the JAK1 tyrosine kinase. Immunoprecipitations of lysates from H2-Kd-expressing or non-expressing cells revealed that only in the presence of H2-Kd SYFPEITHI could be isolated. No longer potential precursor peptide containing SYFPEITHI could be detected. Surprisingly, a peptide lacking the first two amino acids, FPEITHI, was isolated independently of the presence of H2-Kd molecules. The detection of only SYFPEITHI and FPEITHI in cell lysates corresponded with the strong generation of these two peptides in in vitro digests of elongated SYFPEITHI-containing peptides with purified 20S proteasomes. Our results indicate that MHC ligands can be generated directly by the proteasome in vivo and that at least for SYFPEITHI the expression of the corresponding MHC molecule is critical for protection of the ligand in vivo.
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PMID:The making of the dominant MHC class I ligand SYFPEITHI. 971 Feb 25

The type I IFNs represent a primordial, tightly regulated defense system against acute viral infection. IFN-alpha confers resistance to viral infection by activating a conserved signal transduction pathway that up-regulates direct antiviral effectors and induces immunomodulatory activities. Given the critical role of IFN-alpha in anti-human cytomegalovirus (HCMV) immunity and the profound ability of HCMV to escape the host immune response, we hypothesized that HCMV blocks IFN-alpha-stimulated responses by disrupting multiple levels of the IFN-alpha signal transduction pathway. We demonstrate that HCMV inhibits IFN-alpha-stimulated MHC class I, IFN regulatory factor-1, MxA and 2',5-oligoadenylate synthetase gene expression, transcription factor activation, and signaling in infected fibroblasts and endothelial cells by decreasing the expression of Janus kinase 1 and p48, two essential components of the IFN-alpha signal transduction pathway. This investigation is the first to report inhibition of type I IFN signaling by a herpesvirus. We propose that this novel immune escape mechanism is a major means by which HCMV is capable of escaping host immunity and establishing persistence.
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PMID:Human cytomegalovirus inhibits IFN-alpha-stimulated antiviral and immunoregulatory responses by blocking multiple levels of IFN-alpha signal transduction. 1022 53

Ig-like transcript 2 (ILT2)/leukocyte Ig-like receptor 1 (LIR1) is a receptor, specific for MHC class I molecules, that inhibits lymphoid and myeloid cells. Here, we analyzed the molecular and cellular mechanisms by which ILT2 modulates T cell activation in primary CTLs and transfected T cell lines. We found that cross-linking with the TCR and the activity of Src tyrosine kinase p56(lck) were required for phosphorylation of ILT2 and subsequent recruitment of Src homology protein 1. In contrast, ILT2 triggering resulted in reduced phosphorylation of TCRzeta and linker for activation of T cells, which led to reduced TCRzeta-ZAP70 complex formation, as well as extracellular signal-related kinase 1 and 2 activation. Furthermore, ILT2 inhibited both superantigen and anti-TCR Ab-induced rearrangement of the actin cytoskeleton. The inhibitory effect mediated by ILT2 is probably concentrated at the APC-T cell interface because both TCR and ILT2 were strongly polarized toward the APC upon engagement by their specific ligands. Thus, ILT2 inhibits both signaling and cellular events involved in the activation of T cells.
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PMID:Ig-like transcript 2 (ILT2)/leukocyte Ig-like receptor 1 (LIR1) inhibits TCR signaling and actin cytoskeleton reorganization. 1116 Mar 12

To establish new tools for studying human thymic stromal cells, we transfected adherent cells from a human postnatal thymus using a plasmid encoding SV40 large T antigen. Among the cell lines obtained, we characterized four epithelial cell lines (LT-TEC1 to LT-TEC4) and one thymic myoid cell line (MITC). Several morphological, functional and phenotypic differences were observed between these 2 cell types. Epithelial cells were heterogeneous and larger than myoid cells. Untreated LT-TEC lines expressed MHC class I, ICAM-1 and LFA-3 antigens and not MHC class II antigens, similarly to primary thymic epithelial cells (PTEC), while MITC line expressed only class I and LFA-3 antigens. After IFN-gamma treatment, MHC class II and ICAM-1 antigens were markedly upregulated in LT-TEC lines but not in MITC, indicating the absence or a dysfunction of regulatory factors in MITC line. Myoid cells expressed mRNA for all the subunits of the acetylcholine receptor (AChR) while epithelial cells expressed only the alpha, beta and epsilon subunits. Strikingly, LT-TEC produced much more C-C chemokines and IL-6 than MITC cells, while these latter produced higher levels of IL-8 and TNF-alpha. Altogether, these results reveal phenotypic and functional differences between these two stromal cell types, suggesting a potential involvement of myoid cells in the thymic function.
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PMID:Phenotypic and functional characterization of human thymic stromal cell lines. 1129 52


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