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)

Human severe combined immunodeficiency (SCID) can result from mutations in any one of at least seven different genes, including those for adenosine deaminase, the common cytokine receptor gamma chain, Janus kinase 3, IL-7 receptor alpha chain, recombinase activation genes 1 and 2, and CD45. Except for adenosine deaminase, knowledge concerning the latter causes of human SCID has accrued since 1993. Advances in the treatment of this syndrome have been no less significant. Since 1982 it has been possible, by rigorous depletion of T cells from the donor marrow, to use related marrow donors other than HLA-identical siblings for successful treatment of infants with this condition. The success rate with the latter type of transplant exceeds 95% if a transplant can be performed within the first 3.5 mo of life, making early diagnosis crucial. Recently, gene therapy has also been successful in infants with X-linked SCID.
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PMID:Advances in the understanding and treatment of human severe combined immunodeficiency. 1133 59

We have developed an in vivo model of differentiated human acute myeloid leukemia (AML) by retroviral infection of the cytokine-dependent AML cell line TF-1 with the v-Src oncogene. When injected either intravenously or intraperitoneally into 300 cGy irradiated SCID mice, animals formed multiple granulocytic sarcomas involving the adrenals, kidneys, lymph nodes and other organs. The mean survival time was 34+/-10 days (n = 40) after intravenous injection and 24+/-3 days (n = 5) after intraperitoneal injection of 20 million cells. The cells recovered from leukemic animals continued to express interleukin-3 receptors and remained sensitive to the diphtheria fusion protein DT388IL3. Further, these granulocytic sarcoma-derived cells grew again in irradiated SCID mice (n = 10). The cytogenetic abnormalities observed prior to inoculation in mice were stably present after in vivo passage. Similar to the results with v-Src transfected TF-1 cells, in vivo leukemic growth was observed with TF-1 cells transfected with the human granulocyte-macrophage colony-stimulating factor gene (n = 5) and with TF-1 cells recovered from subcutaneous tumors in nude mice (n = 5). In contrast, TF-1 cells expressing v-Ha-Ras (n = 5), BCR-ABL (n = 5), or activated Raf-1 (n = 44) did not grow in irradiated SCID mice. This is a unique, reproducible model for in vivo growth of a differentiated human acute myeloid leukemia and may be useful in the assessment of anti-leukemic therapeutics which have human-specific molecular targets such as the interleukin-3 receptor.
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PMID:Oncogene-dependent engraftment of human myeloid leukemia cells in immunosuppressed mice. 1136 43

The growth factor combination containing early acting cytokines FLT-3 ligand (FL), Stem Cell Factor (SCF) and thrombopoietin (TPO) is able to maintain, for an extended culture period, early stem cells, defined as long-term repopulating NOD/SCID mice (Scid Repopulating Cell-SRC) contained in cord blood (CB). In this culture system, the role of IL-6 and IL-3 has not been clearly established. Using a combination of FL+TPO+SCF with or without IL-6, we were able to form CB CD34+ cells for 30 weeks. The CB CD34+ cells cultured in this system engrafted NOD/SCID mice after 6 weeks of culture; the cells from primary recipients were also able to engraft secondary NOD/SCID mice. When CB CD34+ cells were cultured in the presence of IL-3 in the place of IL-6 we observed an even better expansion of cells and a similar clonogenic progenitor output in the first 8 weeks of culture. However, more primitive LTC-IC output increased up to week 6 with the growth factor combination containing IL-3 and then decreased and disappeared, while with the growth factor combination with or without IL-6 increased up to week 23. Cells cultured for 4 weeks with the 4-factor combination containing IL-3 engrafted NOD/SCID mice less efficiently. Repopulation of NOD/SCID mice was no longer observed when ex vivo expansion was performed for 6 weeks. This study provides some evidence that no differences could be detected in long-term maintenance and even expansion of human primitive cord blood cells cultured with FL+TPO+SCF in the presence or absence of IL-6. Under the culture conditions employed in this study, the presence of IL-3 reduced the repopulating potential of expanded CB CD34+ cells.
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PMID:Different growth factor requirements for the ex vivo amplification of transplantable human cord blood cells in a NOD/SCID mouse model. 1138 43

Human haemopoietic stem and progenitor cells may be distinguished by the pattern of cell surface markers they display. The cells defined as 'stem' cells are heterogeneous and lack specific markers for their detection. However, they may be identified in in vitro assays such as the long-term culture initiating cell (LTC-IC) and in transplant assays involving immunosuppressed NOD/SCID mice. It is still not clear to what extent, if any, these cell populations overlap. The chemokine macrophage inflammatory protein-1alpha (MIP-1alpha) prolongs survival of LTC-IC in suspension cultures and we now show that in longterm bone marrow cultures (LTBMC) maintenance of haemopoiesis was significantly better from the CD34+ cells which possess MIP-1alpha receptors (P < 0.006). We examined one MIP-1alpha receptor, CCR1, which is present on CD34+ cells from haemopoietic tissues. In LTBMC the production of GM-CFC from CD34+CCR1- cells was significantly higher (P < 0.02) than that from CD34+CCR1+ cultures and the incidence of LTC-IC was 3- to 6-fold higher in the CD34+CCR1- cell fraction. In contrast, the cells responsible for high levels of engraftment in NOD/SCID mice were contained in the CD34+CCR1+ cell fraction. The CD34+CCR1+ cells engrafted to high levels in NOD/SCID and generated large numbers of progenitor cells. Therefore, we conclude that LTC-IC and SRC may be distinguished on the basis of expression of the chemokine receptor CCR1.
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PMID:NOD/SCID repopulating cells but not LTC-IC are enriched in human CD34+ cells expressing the CCR1 chemokine receptor. 1145 79

The biodistributions of carborane-containing copper porphyrins, CuTCP and CuTCPH, have been studied previously in mice bearing subcutaneously implanted mammary carcinomas. We now report biodistributions of those porphyrins in Fischer 344 rats bearing intracranial and/or multiple subcutaneous isogeneic 9L gliosarcomas (9LGS). The porphyrin was given either by i.v. infusion or by multiple i.p. injections. When 190 mg CuTCPH/kg body weight was given to the rats by i.v. infusion, median tissue boron concentrations (microg/g) 3 days after the end of infusion were: 64 in subcutaneous tumor, 13 in intracranial tumor, 1 in blood and 3 in brain. When 450 mg CuTCPH/kg body weight was given to the rats by serial i.p. injections, the median concentrations (microg B/g) 4 days after the last injection were: 117 in subcutaneous tumor, 50 in intracranial tumor, 4 in blood, and 4 in brain. CuTCPH biodistribution was also studied in xenografts of the human malignant gliomas U87 and U373, and of the murine EMT-6 mammary carcinoma and the rat 9LGS, each grown subcutaneously in mice with severe combined immunodeficiency (SCIDs). In SCIDs, median boron concentrations (microg/g) 2 days after the last s.c. injection of a total of 190 mg CuTCPH/kg body weight were: 251 in U373, 33 in U87, <0.6 in blood and <0.5 in brain. Because there were such high boron levels in the U373, and because xenografted U373 is similar to spontaneous intracerebral human glioblastoma multiforme (GBM) microscopically, CuTCPH could prove useful as a boron carrier for boron neutron-capture therapy (BNCT) of GBM and of other human malignant gliomas.
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PMID:Biodistribution of copper carboranyltetraphenylporphyrins in rodents bearing an isogeneic or human neoplasm. 1150 10

During the last 10 years, an increasing number of genes have been identified whose abnormalities account for primary immunodeficiencies, with defects in development and/or function of the immune system. Among them is the JAK3-gene, encoding for a tyrosine kinase that is functionally coupled to cytokine receptors which share the common gamma chain. Defects of this gene cause an autosomal recessive form of severe combined immunodeficiency with almost absent T-cells and functionally defective B-cells (T(-)B(+) SCID). Herewith, we present molecular information on the first 27 unique mutations identified in the JAK3 gene, including clinical data on all of the 23 affected patients reported so far. A variety of mutations scattered throughout all seven functional domains of the protein, and with different functional effects, have been identified. Availability of a molecular screening test, based on amplification of genomic DNA, facilitates the diagnostic approach, and has permitted recognition that JAK3 deficiency may also be associated with atypical clinical and immunological features. Development of a structural model of the JAK3 kinase domain has allowed characterization of the functional effects of the various mutations. Most importantly, molecular analysis at the JAK3 locus results in improved genetic counseling, allows early prenatal diagnosis, and prompts appropriate treatment (currently based on hematopoietic stem cell transplantation) in affected families.
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PMID:Mutations in severe combined immune deficiency (SCID) due to JAK3 deficiency. 1166 10

Defects of the JAK3-gene are known to cause an autosomal recessive form of severe combined immunodeficiency with almost absent T-cells and functionally defective B-cells (T-B+SCID). The JAK3 protein, an intracellular tyrosine kinase, is crucial for signal-transmission from the common gamma chain to the Signal Transducers and Activators of Transcription (STATs) that drive gene expression in the nucleus. We present nine novel patients with eleven distinct mutations (g.96A>G, g.268G>C, IVS12-1G>A, g.2046C>T, g.2160C>T, g.2175G>A, g.2187G>T, g.2391C>T, g.2406C>T, IVS18+3G>C) among them a mutation in the kinase domain (JH1: g.3167del). The clinical phenotype of the patients shows an unusually broad spectrum ranging from classical SCID to almost normal. In order to understand the complex genotype-phenotype correlation we studied expression and function (by IL-2 induced phosphorylation) of the newly identified and two other alleles with JH1 mutations we recently reported. We found the first mutation in the JH1-domain of JAK3, that precludes kinase activity (L910S). The two other JH1 mutations both caused a premature stop. One of them (C1024fsX1037) also abolished any phosphorylation of JAK3 and expression of the protein. The other mutation (Y1023X), affecting the last JH1 tyrosine, may allow for residual protein expression and phosphorylation. This may indicate that the part of the kinase region downstream Y1023, is not essential for the function of JAK3.
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PMID:Eleven novel JAK3 mutations in patients with severe combined immunodeficiency-including the first patients with mutations in the kinase domain. 1166 21

The migration of immunocytes within the extracellular matrix (ECM) is influenced by the activation state of the incoming cell and its responses to the presence of chemokines and cytokines. We studied the regulatory role of TGF-beta1 on T cell homing to secondary lymphatic organs, such as the spleen, and chemotaxis within an ECM-like environment in using an ECM-like 3-dimensional gel system designed to follow the migration of individual leukocytes along chemokine gradients in real time. The numbers of migrating naive, but not memory T cells toward SDF-1alpha markedly increased after pre-incubating the cells with TGF-beta1 (0.25 ng/ml) for 24 h. The mechanisms underlying TGFbeta1-modulated migration involve the up-regulation of the expression of the SDF-1alpha receptor CXCR4, the enhancement of the SDF-1alpha-induced actin polymerization, and increased phosphorylation of Pyk2, a focal adhesion kinase involved in integrin-mediated lymphocyte migration, adhesion and interactions with ECM. Interestingly, priming of naive human T cells with TGF-beta1 increased homing of these cells to the spleen of NOD/SCID mice in a CXCR4-dependent manner. We propose that the effect of TGF-beta1 on the chemotaxis of naive T cells may be important in the locomotion of naive T cells toward SDF-1alpha-rich niches.
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PMID:TGF-beta1 enhances SDF-1alpha-induced chemotaxis and homing of naive T cells by up-regulating CXCR4 expression and downstream cytoskeletal effector molecules. 1175 60

It has been established that the BCR-ABL oncogene produced on the Philadelphia chromosome in human chronic myeloid leukemia(CML) directly causes leukemic transformation of multipotential progenitor cells. In order to study the molecular basis of this process, many convenient and useful biological assays have been found, including transformation of mouse bone marrow cells in primary culture and of Rat1 fibroblasts, cytokine-independent growth of dependent cell lines, retrovirus-mediated murine CML model, and transgenic mice model. New biological activities such as anti-apoptosis, anti-DNA repair, differentiation of ES cells may further give supportive explanations for clinical manifestation of CML. NOD/SCID transplantation model and conditional transgenic model may be the current best animal system by which to investigate cell dynamics in the most strict and natural circumstances.
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PMID:[Experimental systems in CML biology]. 1176 33

Chronic myelogenous leukemia (CML) is a hematopoietic malignant disease associated with expression of a chimeric BCR-ABL gene. We recently succeeded in designing a novel allosterically controllable ribozyme, the maxizyme (Tanabe et al. Biomacromolecules 2000, 1, 108-117; Kuwabara et al. Biomacromolecules 2001, 2, 788-799), that not only specifically cleaves BCR-ABL mRNA and induces apoptosis in cultured CML cells but also shows significant inhibition against the growth of an established BV173 cell line in a mouse model (Tanabe et al. Nature 2000, 406, 473-474). As an extension of our studies, we tested the maxizyme against primary CML cells in the same mouse model. The maxizyme under the control of a tRNA(Val) promoter showed significant inhibition against the growth of the primary bone marrow cells from a Japanese patient with CML. Specifically, to examine the applicability of the maxizyme in the treatment of CML, we assessed the antitumor effect of the maxizyme in murine models of CML. Fourteen weeks after the injection of primary CML cells into a NOD-SCID mouse, the bone marrow of the mouse was filled with primary CML cells as a result of diffuse leukemia. In marked contrast, when maxizyme-expressing primary CML cells were injected, the mouse remained disease-free. These results further strengthen our earlier suggestion that the maxizyme technology might provide a useful approach to the treatment of CML.
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PMID:Allosterically controllable maxizyme-mediated suppression of progression of leukemia in mice. 1177 96


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