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)

We report the biological characteristics of leukaemic blasts from two cases of acute leukaemia with an interstitial deletion of the long arm of chromosome 9 (9q-). Case 1 (FAB: M1) showed del(9)(q12q22) as the sole karyotypic anomaly, and case 2 (FAB: M1) presented del(9) (q12q22) in association with trisomy 10. In both cases, leukaemic blasts presented unique cytological features, such as prominent vacuoles on Giemsa staining, or strong localization of myeloperoxidase resembling 'pseudo-Chediak-Higashi' granules. Immunophenotyping of blasts revealed the biphenotypic expression of T-lymphoid/myeloid antigens (CD2, CD7/CD33) in addition to CD34. Neither T-cell receptor beta (TCRB), T-cell receptor gamma (TCRG) nor Ig heavy chain (IGH) genes were clonally rearranged. Furthermore, there was neither rearrangement nor expression of ABL, which is located at 9q34, indicating that the deletion involved bands centrometric to 9q34 did not induce the activation of ABL. DNA synthesis of the blasts was stimulated (stimulation index greater than 2.0) in the presence of interleukin (IL)-3, IL-4, granulocyte colony-stimulating factor or erythropoietin (Epo). IL-3 and IL-4 could also support the in vitro growth of leukaemic blast colonies, and the IL-3- or IL-4-dependent blast colony growth was synergistically enhanced by the addition of IL-6 or Epo. These observations imply that T-lymphoid/myeloid or pluripotent stem cells may be closely involved in the development of 9q- AML.
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PMID:Interstitial 9q deletion in T-lymphoid/myeloid biphenotypic leukaemia. 155 Jul 72

Previous studies have revealed a consistent defect in the cycling behavior of primitive neoplastic progenitor cells in patients with Philadelphia chromosome (Ph1)-positive chronic myeloid leukemia (CML). This is manifested both in vivo and in long-term cultures of CML cells as an increased rate of turnover amongst Ph1-positive progenitor cell types whose counterparts in normal individuals are mainly quiescent. To determine whether this deregulated proliferative activity of primitive Ph1-positive cells might be explained by a perturbation in the production of growth factors that regulate the turnover of primitive normal cells, the possibility of either autocrine or paracrine mechanisms of Ph1-positive cell stimulation was investigated. Northern blot analysis of total cellular RNA extracted from various CML blood cell populations showed no evidence of increased expression of granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage-CSF (GM-CSF), interleukin-1 alpha (IL-1 alpha), IL-1 beta, IL-3, IL-6, or tumor necrosis factor-alpha (TNF-alpha) compared with analogous normal peripheral blood cell populations in which transcripts for most of these growth factors are not detectable. A similar analysis of RNA extracted from the adherent layer of 4-week-old long-term cultures established from CML marrow (in which the Ph1-positive cells typically disappear) or from CML blood seeded onto normal marrow adherent layers (in which Ph1-positive cells typically persist) also revealed no difference in growth factor production compared with analogous cultures established with exclusively normal cells. For some of the growth factors studied, the assessment of bioactivity detectable in the medium confirmed the RNA data. There was also no evidence of a decreased production of putative inhibitors of primitive hematopoietic cells, i.e. transforming growth factor-beta and macrophage inflammatory protein-1 alpha by CML versus normal cells or cultures. These results do not support the existence of BCR-ABL induced autocrine or paracrine mechanisms in CML and suggest that constitutive activation of events normally dependent on growth factor receptor stimulation is more likely to underlie the lack of proliferation control exhibited by primitive Ph1-positive cells.
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PMID:Lack of evidence for abnormal autocrine or paracrine mechanisms underlying the uncontrolled proliferation of primitive chronic myeloid leukemia progenitor cells. 196 Oct 20

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

The basic tenet underlying the present work and supported by recent studies is that there is a dialogue between developing thymocytes and thymic stromal cells. One direction in this dialogue, i.e. thymic stromal cell role in shaping thymocyte maturation, has been extensively studied. The other direction, thymocyte effect on stromal cell development and function, started to emerge only recently on the basis of in vivo observations in SCID and knockout mice. An in vitro approach to the analysis of this interaction may add substantial insight into the process, as demonstrated by the present work. We made use of a culture system of either murine thymic epithelial cells (TEC line) cultured alone or cocultured with thymocytes. Unstimulated thymocytes or their supernatant caused 40-80% inhibition of TEC cell proliferation, as measured by 3H-thymidine incorporation. Cell cycle analysis by flow cytometry indicated that this inhibition can be attributed to reduction in G2/M phase cell number pari passu with an increase in Go/G1 cell number. This inhibitory effect was found to be partially mediated by TGF-beta produced by thymocytes. On the other hand, thymocytes augmented IL-6 production by TEC cells in coculture, an effect which could not be reproduced by thymocyte culture supernatant and was not inhibited by thymocyte pretreatment with formaldehyde or emetine. Furthermore, antibodies against thymocyte adhesion molecules (CD2, LFA-1) blocked the thymocyte-induced IL-6 secretion. IL-6 was found to be an autocrine growth factor of TEC in culture, since a combination of anti IL-6 and anti IL-6 receptor antibodies caused 70% inhibition of TEC proliferation and addition of exogenous recombinant IL-6 doubled the rate of proliferation. These results suggest that thymocytes regulate thymic epithelial cell growth by a complex set of inhibitory and enhancing signals mediated through either soluble factors or direct contact. The ultimate effect is dependent on the balance between different signals and may be different in different microenvironmental settings in vivo. In coculture in vitro the dominant effect was growth inhibition of the epithelial cells by thymocytes.
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PMID:The role of thymocytes in regulating thymic epithelial cell growth and function. 763 Nov 52

To investigate the role of B cells in the development of experimental Staphylococcus aureus-induced arthritis, we used X-linked immunodeficiency (xid) mice that carry a Bruton's tyrosine kinase mutation affecting the function of B cells. NFR/N.xid and congenic NFR/N mice were inoculated i.v. with a toxic syndrome toxin-1 producing S. aureus LS-1 strain. B cell-deficient NFR/N.xid mice developed less frequent (p < 0.01) and less severe (p < 0.01) arthritis than NFR/N mice did. These clinical findings were corroborated by histopathologic evaluation, indicating that NFR/N.xid mice had significantly lower (p < 0.01) erosivity of the disease. Interestingly, infected NFR/N.xid mice showed decreased bacterial burden in blood, joints, and other organs compared with the control mice. Serologic studies displayed poor B cell responses to staphylococcal cell walls, toxic shock syndrome toxin-1, and ssDNA, accompanied by a low level of Igs in infected NFR/N.xid mice. More importantly, xid defect affected cytokine profile. The in vitro experiments showed that the lymphocytes from NFR/N.xid mice had low IL-6, but high IFN-gamma production upon stimulation with staphylococcal cell walls compared with NFR/N mice. Furthermore, the in situ hybridization technique revealed the relative increase of IFN-gamma, but marked decrease of IL-1 beta mRNA expression in spleens of infected NFR/N.xid mice. No significant difference in IL-4, IL-10, and TNF-alpha mRNA expression was found between both strains. Our findings demonstrate that B cells may, directly or indirectly, contribute to the pathogenesis of septic arthritis. The results indicate that increased IFN-gamma production along with low IL-6 and IL-1 beta synthesis found in xid mice may provide a more favorable outcome of S. aureus arthritis.
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PMID:Mice with the xid B cell defect are less susceptible to developing Staphylococcus aureus-induced arthritis. 763 57

To determine the specificity of signal transducer and activator of transcription (STAT) protein activation by box 3 motif-deficient hematopoietin receptors, expression vectors encoding the receptors for growth hormone, interleukin-3 (IL-3), and IL-4 were transiently transfected into COS-1 cells, together with expression vectors for Janus kinases (JAKs) and STAT proteins. Each receptor mediated a dose-dependent activation of STAT1 and STAT3, and for IL-3R and GHR this process was enhanced by JAK2. The data suggest that a box 3 motif in the cytoplasmic domain of the signal-transducing receptor to the JAK/STAT pathway. Transfection of the receptors, in combination with STAT3, into HepG2 cells reconstituted a cytokine-dependent stimulation of gene transcription through IL-6 response elements, providing evidence for a functional role of STAT3 in controlling gene expression.
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PMID:Receptors for interleukin-3 (IL-3) and growth hormone mediate an IL-6-type transcriptional induction in the presence of JAK2 or STAT3. 765 99

The gene regulatory functions of the human IL-2 receptor (IL-2R) were reconstituted in transiently transfected hepatoma cells. The combination of IL-2R beta and -gamma mediated a strong stimulation via the cytokine response element of the alpha 1-acid glycoprotein gene and the hematopoietin receptor response element, but none via the IL-6 response element or the sis-inducible element. IL-2R alpha enhanced 10-fold the sensitivity of the IL-2R beta.gamma complex to respond to IL-2 or IL-15, but did not modify the specificity or the magnitude of maximal gene regulation. A homodimerizing chimeric receptor G-CSFR-IL-2R beta could mimic the IL-2R action. The IL-2R-mediated gene regulation was similar to that seen with receptors for IL-4 and IL-7, but differed from that for IL-6 type cytokines, thrombopoietin, erythropoietin, and growth hormone. The activation of STAT proteins by the IL-2R was assessed in transfected L-cells and COS-1 cells. Although IL-2R subunits were highly expressed in these cells, no STAT protein activation was detectable. Transient overexpression of JAK3 was unable to change the signaling specificity of the hematopoietin receptors in rat hepatoma, L-, and COS cells, but established a prominent activation of the IL-6 response elements by the IL-2R and IL-4R in HepG2 cells. The data support the model that the IL-2R and related hematopoietin receptors produce at least two separate signals which control gene expression.
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PMID:The action of interleukin-2 receptor subunits defines a new type of signaling mechanism for hematopoietin receptors in hepatic cells and fibroblasts. 771 38

The cytoplasmic receptor sequences required for the transcriptional control via the IL-6 response element (IL-6RE) and the hematopoietin receptor response element (HRRE) in hepatoma cells were defined by transient expression of wild-type and mutant granulocyte-colony stimulating factor receptor-gp130 chimeric receptors. gp130 generated two separate transcriptional signals, one of which was directed to IL-6RE and required an intact box 3 motif, and another, which was directed to HRRE and was box 3-independent. The activation of DNA-binding of STAT3 required the same gp130 domains as the IL-6RE response. A box 3-independent activation of STAT proteins was achieved by overexpression of the kinases JAK2 or TYK2. The increase in the DNA-binding activity of STAT proteins, however, did not result in a corresponding increase in transcription via either IL-6RE or HRRE. The data indicate that activation of the DNA-binding potential of STAT proteins via gp130 is not sufficient to achieve transcriptional up-regulation of specific target genes.
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PMID:Separate signaling mechanisms are involved in the control of STAT protein activation and gene regulation via the interleukin 6 response element by the box 3 motif of gp130. 779 60

Signaling by a wide variety of cytokines, including interferons, interleukins, and growth factors, involves activation of JAK kinases and Stat (Signal transducers and activators of transcription) proteins. At present, not much is known about the molecular mechanisms by which interleukin-5 (IL-5) exerts its diverse biologic effects. Human eosinophils are one of the most important target cells for IL-5 and were used here to study IL-5 signaling in a primary human cell. IL-5 induced rapid and transient tyrosine phosphorylation of JAK2. Moreover, IL-5 induced at least two DNA-binding complexes, using nuclear extracts from normal human eosinophils and the IL-6/interferon-gamma response element of the ICAM-1 promoter (ICAM-1 pIRE) in an electromobility shift assay. From supershift experiments it was concluded that one DNA-binding complex contained Stat1 alpha, probably as a homodimer. Both DNA-binding complexes were inhibited by a phosphotyrosine antibody (4G10), suggesting that tyrosine phosphorylation is required for complex formation. IL-3 and granulocyte-macrophage colony-stimulating factor induced, similar to IL-5, two DNA-binding complexes in human eosinophils, including Stat1 alpha. These data show for the first time that molecular mechanisms of IL-5 signaling in human eosinophils involve members of the JAK kinase family as well as members of the Stat family.
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PMID:Interleukin-5 signaling in human eosinophils involves JAK2 tyrosine kinase and Stat1 alpha. 788 66

We have previously shown that the IL-6R in a growth-responsive B cell line, AF10, induces activation of mitogen-activated protein (MAP) kinase. Here we demonstrate the activation of Raf-1 and MEK-1, which act as a MAP kinase kinase kinase and a MAP kinase kinase, respectively, in the MAP kinase cascade induced by IL-6 in AF10 cells. IL-6 also induced tyrosine phosphorylation of the signaling transducing subunit of the IL-6R in AF10 cells, along with tyrosine phosphorylation of the gp130-associated tyrosine protein kinase JAK1 and the adaptor molecule p52shc. Although induction of tyrosine phosphorylation and activation of MAP kinase by IL-6 in a differentiation-responsive B cell line, SKW 6.4, were below the limits of detection, the phorbol ester PMA did activate Raf-1, MEK-1, and MAP kinase without inducing the phosphorylation of gp130, JAKs, or p52shc. These results suggest that JAK kinase family members associated with the IL-6R may participate in the activation of MAP kinase in AF10 cells by way of an adaptor protein and Ras-dependent kinase cascade.
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PMID:Involvement of Janus kinases, p52shc, Raf-1, and MEK-1 in the IL-6-induced mitogen-activated protein kinase cascade of a growth-responsive B cell line. 796 20


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