Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.2 (focal adhesion kinase)
 44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Eight patients with relapsed chronic myelogenous leukemia (CML) after allogeneic bone marrow transplantation (BMT) were treated with alpha-interferon and leukocyte transfusions of the bone marrow donor. Six patients responded with disappearance of leukemic cells (Ph1, BCR-ABL) and reestablished donor hemopoiesis. All six patients developed bone marrow hypoplasia and graft-versus-host disease (GvHD). Three of the six patients died of cerebral bleeding, infection and GvHD, respectively. The remaining three patients are alive and well at day 418, 677, 818 after leukocyte transfusions. Two patients relapsed with more advanced disease of CML after BMT and failed treatment. Donor leukocyte transfusions provide an effective therapy for patients with relapsed CML after BMT, but are associated with a high mortality due to bone marrow hypoplasia and GvHD.
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PMID:[Leukocyte transfusion as therapy of recurrent CML after allogenic bone marrow transplantation]. 948 Jan 8

Interferon-alpha treatment induces complete cytogenetic remission in 25% of Philadelphia chromosome (Ph)-positive chronic myelogenous leukemia (CML) patients. These remissions are durable unlike remissions induced with other therapies and yet residual leukemia is detectable in most of these patients. Total peripheral blood mononuclear cells (PBMCs) from CML patients in long-term remission following interferon treatment exhibited significantly higher proliferative responses (four- to 15-fold over background) than normals directed against P210 BCR-ABL in extracts of transfected monkey fibroblast cells. Surprisingly, similar enhanced levels of specific proliferative responses were observed with extracts from cells expressing Bcr and/or Abl proteins. In contrast, extracts from vector only or v-Mos-expressing cells had background level responses. Control monkey fibroblast cells lacking BCR-ABL expression failed to induce proliferation over background levels. Normal individuals had no significant responses to Bcr/Abl extracts. On the other hand, peripheral blood mononuclear cells from allogeneic bone marrow transplant CML patients had proliferative responses to cell extracts independent of Bcr-Abl. These data indicate that patients in remission due to alpha-interferon treatment have significantly higher levels of specific cellular immunoreactivity against Bcr/Abl sequences than normal controls, which could play a role in maintaining cytogenetic remission in Ph-positive CML patients.
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PMID:Evidence for specific immune response against P210 BCR-ABL in long-term remission CML patients treated with interferon. 951 77

Interferon-gamma (IFNgamma) transmits its signal through a specific cell surface receptor (IFNgammaR), which consists of a primary ligand binding alpha-chain (IFNgammaR alpha) and a signaling beta-chain (IFNgammaR beta). Recent studies identified the cytokines IFNgamma, interleukin-6 (IL-6), IL-1alpha, and tumor necrosis factor-alpha in testicular cells. Therefore, we: 1) examined the expression of IFNgammaR alpha and IFNgammaR beta subunits in freshly isolated and purified rat testicular cells; 2) examined the differential regulation of receptor components by cytokines using primary cultures of Sertoli cells; 3) identified the cell signaling pathway components of testicular IFNgammaR; and 4) characterized the functional role of testicular IFNgamma using primary Sertoli cells. We demonstrated the messenger RNAs for both chains of IFNgammaR in rat testicular cells using Northern hybridization analysis. Western blot analysis and immunocytochemistry showed that both specific IFNgammaR protein subunits were present in cultured primary Leydig and Sertoli cells prepared from the testes of immature rats. The expression of both IFNgammaR component messenger RNAs in cultured Sertoli cells was increased by its specific ligand (IFNgamma), as well as IL-1alpha and tumor necrosis factor-alpha, in both a time- and dose-dependent manner. IFNgamma-activation of the Janus (JAK) tyrosine kinases, JAK1 and JAK2 proteins, indicate that IFNgammaR, expressed in the Sertoli cell, is functional. Moreover, IFNgamma modulates the expression of interferon regulatory factor (IRF)-1 and IL-1beta converting enzyme genes in Sertoli cells. Thus, our data are suggestive of a role(s) for IFN-gamma in the regulation of distinct gene expression and cell-specific sensitivity to apoptosis in the testis.
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PMID:Identification and regulation of testicular interferon-gamma (IFNgamma) receptor subunits: IFNgamma enhances interferon regulatory factor-1 and interleukin-1beta converting enzyme expression. 956 81

The cytoplasmic protein tyrosine kinase Syk has two amino-terminal SH2 domains that engage phosphorylated immunoreceptor tyrosine-based activation motifs in the signaling subunits of immunoreceptors. Syk, in conjunction with Src family kinases, has been implicated in immunoreceptor signaling in both lymphoid and myeloid cells. We have investigated the role of Syk in Fcgamma receptor (FcgammaR)-dependent and -independent responses in bone marrow-derived macrophages and neutrophils by using mouse radiation chimeras reconstituted with fetal liver cells from Syk-/- embryos. Chimeric mice developed an abdominal hemorrhage starting 2 to 3 months after transplantation that was ultimately lethal. Syk-deficient neutrophils derived from the bone marrow were incapable of generating reactive oxygen intermediates in response to FcgammaR engagement but responded normally to tetradecanoyl phorbol acetate stimulation. Syk-deficient macrophages were defective in phagocytosis induced by FcgammaR but showed normal phagocytosis in response to complement. The tyrosine phosphorylation of multiple cellular polypeptides, including the FcgammaR gamma chain, as well as Erk2 activation, was compromised in Syk-/- macrophages after FcgammaR stimulation. In contrast, the induction of nitric oxide synthase in macrophages stimulated with lipopolysaccharide and gamma interferon was not dependent on Syk. Surprisingly, Syk-deficient macrophages were impaired in the ability to survive or proliferate on plastic petri dishes. Taken together, these results suggest that Syk has specific physiological roles in signaling from FcgammaRs in neutrophils and macrophages and raise the possibility that in vivo, Syk is involved in signaling events other than those mediated by immunoreceptors.
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PMID:The Syk protein tyrosine kinase is essential for Fcgamma receptor signaling in macrophages and neutrophils. 963 5

Using the LXSN backbone, a defective retroviral vector (LISN) was constructed that encodes the human interferon (IFN)-alpha2 (hIFN-alpha2) gene and the neomycin resistance gene; the hIFN-alpha2 gene was cloned from human placental genomic DNA. High titers of the LISN retrovirus were produced by the amphotropic packaging cell line GP+envAM12. LISN is able to infect three human hematopoietic and leukemic cell lines: K562, LAMA-84, and TF-1. G418-resistant cells were detected in a similar proportion after infection with either the LISN retroviral vector or the LnLSN retroviral vector (encoding the nlsLacZ gene instead of hIFN-alpha2), suggesting that hIFN-alpha2 does not inhibit (or only partially inhibits) the production of retroviral particles by the packaging cell line and the infection of human cells. LISN-infected cells express and secrete hIFN-alpha2 as demonstrated by Northern blot analysis of poly(A)+ RNA, detection of the intracellular protein by fluorescence-activated cell sorter analysis, and detection of secreted hIFN-alpha in cell supernatants using an enzyme-linked immunosorbent assay. Retrovirally produced hIFN-alpha2 is biologically active, as demonstrated by the partial inhibition of the growth of K562 and TF-1, the modulation of the expression of cell surface antigens, the induction of the (2'-5') oligoadenylate synthetase, and, for LAMA-84, the down-modulation of the BCR-ABL protein. We conclude that the infection of human leukemic cell lines with a retroviral vector encoding hIFN-alpha2 is feasible and induces the expected biological effects. This experimental model will be useful in investigating the possibility of transducing normal and leukemic cells and hematopoietic progenitors and in determining the consequences of the autocrine production of hIFN-alpha2 on the behavior of these cells.
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PMID:A defective retroviral vector encoding human interferon-alpha2 can transduce human leukemic cell lines. 969 76

The biological target for interferon (IFN)-alpha in chronic myeloid leukemia (CML) is unknown, but one possibility is that amplification of granulocyte-macrophage colony-forming cells (CFU-GM) is reduced. Replating CFU-GM colonies and observing secondary colony formation provides a measure of CFU-GM amplification. Amplification of CML, but not normal, CFU-GM in vitro was significantly inhibited by IFN-alpha (P = 0.02). In 5 out of 15 CML cases studied by fluorescence in situ hybridization, in vitro treatment with IFN-alpha increased the proportion of CFU-GM, which lacked BCR-ABL. The ability of patients' CFU-GM to amplify, and suppression of this ability by IFN-alpha, predicted responsiveness to IFN-alpha therapy in 86% of cases. Investigation of patients on treatment with IFN-alpha showed a threefold reduction in CFU-GM amplification in responders (P = 0.03) but no significant change in nonresponders (P = 0.8). We conclude that IFN-alpha preferentially suppresses amplification of CML CFU-GM to varying degrees. The differing in vitro sensitivities to IFN-alpha and growth kinetics of individual patients' cells could help differentiate those who will or will not benefit from treatment with IFN-alpha.
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PMID:Treatment with interferon-alpha preferentially reduces the capacity for amplification of granulocyte-macrophage progenitors (CFU-GM) from patients with chronic myeloid leukemia but spares normal CFU-GM. 971 Apr 39

It has been shown that interferons (IFNs) exert their signals through receptor-associated Janus kinases (JAKs) and signal transducers and activators of transcription (STATs). However, molecular mechanism of regulation of IFN signaling has not been fully understood. We have reported novel cytokine-inducible SH2 protein (CIS) and JAK binding protein (JAB) family genes that can potentially modulate cytokine signaling. Here we report that JAB is strongly induced by IFN-gamma but not by IFN-beta in mouse myeloid leukemia M1 cells and NIH-3T3 fibroblasts. NIH-3T3 cells ectopically expressing JAB but not CIS3 lost responsiveness to the antiviral effect of IFN-beta and IFN-gamma. M1 leukemic cells stably expressing JAB were also resistant to IFN-gamma and IFN-beta-induced growth arrest. In both NIH-3T3 and M1 transformants expressing JAB, IFN-gamma did not induce tyrosine phosphorylation and DNA binding activity of STAT1. Moreover, IFN-gamma-induced activation of JAK1 and JAK2 and IFN-beta-induced JAK1 and Tyk2 activation were inhibited in NIH-3T3 JAB transformants. These results suggest that JAB inhibits IFN signaling by blocking JAK activity. We also found that IFN-resistant clones derived from LoVo cells and Daudi cells expressed high levels of JAB without stimulation. In IFN-resistant Daudi cells, IFN-induced STAT1 and JAK phosphorylation was partially reduced. Therefore, overexpression of JAB could be, at least in part, a mechanism of IFN resistance.
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PMID:A Janus kinase inhibitor, JAB, is an interferon-gamma-inducible gene and confers resistance to interferons. 971 95

Progress has been made in understanding BCR-ABL-positive leukemias. A new transcript (p230BCR-ABL) has been characterized that is associated with Ph-positive chronic neutrophilic leukemia. The ATM protein appears to be a regulator of ABL activity in response to irradiation damage. Pathways linking BCR-ABL to the BCL-2 family of proteins may be active in Philadelphia-positive cells and inhibit apoptosis. The 62-kD protein constitutively phosphorylated in chronic myeloid leukemia progenitors has been cloned. Ph-negative long-term culture-initiating cells are detectable in many chronic myeloid leukemia patients. The combination of interferon alfa and cytarabine appears to be superior to interferon alfa alone. Autografting with in vivo-purged stem cells may induce prolonged remissions. Specific inhibitors of the BCR-ABL tyrosine kinase are becoming available.
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PMID:Chronic myeloid leukemia. 974 37

During the past 4 years, significant progress has been made in elucidating the earliest events following binding of ligands to members of the cytokine receptor superfamily. This is a rapidly growing family of receptors that currently includes receptors for growth hormone (GH); prolactin; erythropoeitin; granulocyte colony-stimulating factor; granulocyte macrophage colony-stimulating factor; interleukin(IL)s 2-7, 9-13, 15; interferon (IFN)-alpha, beta, and gamma; thrombopoietin; leptin; oncostatin M; leukemia inhibitory factor (LIF); ciliary neurotrophic factor; and cardiotropin-1. Despite their diverse physiological effects in the body, ligands that bind to members of this family share multiple signaling pathways. An early and most likely initiating event for all of them is the activation of one or more members of the Janus (or JAK) family of tyrosine kinases. The activated JAK kinases, which form a complex with the cytokine receptor subunits, phosphorylate themselves as well as the receptor. These phosphorylated tyrosines form binding sites for various signaling molecules that are themselves thought to be phosphorylated by JAK kinases, including 1) signal transducers and activators of transcription (Stats), which regulate transcription; 2) She proteins that recruit Grb2-SOS complexes, thereby initiating the Ras-MAP kinase pathway; and 3) insulin receptor substrate (IRS) proteins that are thought to regulate metabolic events in the cell. Additional other signaling molecules have been implicated in signaling by some cytokines, including protein kinase C, SH2-B beta, and intracellular Ca. This review uses the GH receptor as a model system for studying cytokine signaling and summarizes some of the data used to establish JAK2 as a GH receptor-associated tyrosine kinase and to identify signaling molecules that lie downstream of JAK2. Since these pathways are shared by multiple cytokines, this review also discusses factors that might contribute to specificity of response to different cytokines.
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PMID:Signaling via JAK tyrosine kinases: growth hormone receptor as a model system. 976 3

The beta-R1/I-TAC (interferon-inducible T-cell alpha-chemoattractant) gene encodes an alpha-chemokine that is a potent chemoattractant for activated T-cells. We previously reported that beta-R1 was selectively induced by interferon (IFN)-beta compared with IFN-alpha and that the canonical type I IFN transcription factor interferon-stimulated gene factor 3 (ISGF3) was necessary but not sufficient for beta-R1 induction by IFN-beta. These findings suggested that beta-R1 induction by IFN-beta required an accessory component. To begin characterizing this signaling pathway, we examined the function of TYK2 protein in the IFN-beta-mediated induction of beta-R1. This study was motivated by the observation that beta-R1 could not be induced in TYK2-deficient U1 cells by IFN-beta (Rani, M. R. S., Foster, G. R., Leung, S., Leaman, D., Stark, G. R., and Ransohoff, R. M. (1996) J. Biol. Chem. 271, 22878-22884), an unexpected result because IFN-beta evokes substantial expression of IFN-stimulated genes (ISGs) in U1 cells through a TYK2-independent pathway. We now report beta-R1 expression patterns in U1 cells complemented with wild-type or mutant TYK2 proteins. Complementation with wild-type TYK2 rescued IFN-beta-inducible expression of beta-R1. Cells expressing kinase-deficient deletion or point mutants of TYK2 were refractory to induction of beta-R1 by IFN-beta despite robust expression of other ISGs. Transient transfection analysis of a beta-R1 promoter-reporter confirmed that transcriptional activation of beta-R1 by IFN-beta required competent TYK2 kinase. These studies indicate that the catalytic function of TYK2 is required for IFN-beta-mediated induction of beta-R1. Catalytic TYK2 is the first identified component in an accessory signaling pathway that supplements ISGF3/interferon-stimulated response element signaling for gene induction by type I IFNs.
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PMID:Induction of beta-R1/I-TAC by interferon-beta requires catalytically active TYK2. 989 Sep 42


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