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)

SOCS-1 is an inducible SH2-containing inhibitor of Jak kinases and as such can potently suppress cytokine signaling. SOCS-1 deficient mice die within the first three weeks of life from a myeloproliferative disorder driven by excessive interferon signaling. We report here that SOCS-1 inhibits proliferation signals induced by a variety of oncogenes active within the hematopoietic system. Ectopic expression of SOCS-1 abolished proliferation mediated by a constitutively active form of the KIT receptor, TEL-JAK2, and v-ABL, and reduced metastasis from BCR-ABL transformed cells. SOCS-1, however, did not interfere with v-SRC or RASV12 mediated cellular transformation. A mutant form of SOCS-1 unable to bind through its SH2 domain to tyrosine phosphorylated proteins could still inhibit KIT, but not TEL-JAK2, indicating multiple mechanisms for SOCS-1-mediated tumor suppression. We show that the steady state levels of TEL-JAK2 and to a greater extent v-ABL are diminished in the presence of SOCS-1. Lastly, we show that SOCS-1 -/- fibroblasts are more sensitive than wild type fibroblasts to either spontaneous or oncogene-induced transformation. These data suggest that loss-of-function of SOCS-1 may collaborate with a variety of hematopoietic oncogenes to facilitate tumor progression.
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PMID:The tumor suppressor activity of SOCS-1. 1208 Apr 66

Chronic myeloid leukaemia (CML) is characterised by the occurrence of the Philadelphia (Ph) chromosome (9/22 translocation) and the formation of a fusion protein--the BCR-ABL transcript with constitutive activation of the BCR-ABL tyrosine kinase and consequent changes in the intracellular signal transduction, which is responsible for the deregulated myeloid cell proliferation. STI571 (signal transduction inhibition number 571) is a potent and selective inhibitor of the BCR-ABL tyrosine kinase. In the chronic phase of the disease, normal peripheral blood values are achieved within the first month of treatment in the large majority of patients and in many patients also a cytogenic response within the following months. The results in the advanced phase are far less favourable, which is explained by the development of resistance owing to reactivation of the BCR-ABL signal transduction. Side effects are primarily nausea, vomiting, various rashes, oedema, most often in the periorbital region, and musculoskeletal symptoms, including muscle cramps. Perspectives for treatment with STI571 are described, as are combinations with alpha-interferon and other cytostatics with a synergistic profile.
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PMID:[STI571 (Glivec)--a new drug for the treatment of chronic myeloid leukemia]. 1208 21

It is well established that IFNalpha has significant clinical activity in the treatment of chronic myelogenous leukemia (CML). This cytokine has been used for many years in the management of patients in the chronic phase of the disease, but the mechanisms by which it induces growth inhibitory effects in CML-cells have not been elucidated. Understanding the signaling mechanisms by which the Type I IFN receptor transduces growth inhibitory signals in BCR-ABL expressing cells should prove very valuable, as it may result in the design of new, more specific pharmacological compounds that target the same cellular cascades. Recent evidence indicates that, in addition to the classic IFN-activated Jak-Stat pathway, the Type I IFN receptor engages in its signaling cascade the CrkL-adapter protein, which is also a substrate for the kinase activity of the BCR-ABL oncogene. In addition, it appears that activation of a member of the Map kinase (MAPK) family of proteins, the p38 MAPK, is essential for the generation of the antileukemic effects of IFNalpha. This review summarizes the recent advances in the-field of interferon signaling in CML cells and discusses the implications of identifying signaling proteins that mediate IFNalpha-induced growth inhibition.
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PMID:Signaling via the interferon-alpha receptor in chronic myelogenous leukemia cells. 1215 54

A role for alpha/beta interferon (IFN-alpha/beta) in the IFN-gamma antiviral response has long been suggested. Accordingly, possible roles for autocrine or double-stranded-RNA (dsRNA)-induced IFN-alpha/beta in the IFN-gamma response were investigated. Use was made of wild-type and a variety of mutant human fibrosarcoma cell lines, including mutant U5A cells, which lack a functional IFN-alpha/beta receptor and hence an IFN-alpha/beta response. IFN-gamma did not induce detectable levels of IFN-alpha/beta in any of the cell lines, nor was the IFN-gamma response per se dependent on autocrine IFN-alpha/beta. On the other hand, a number of responses to dsRNA [poly(I). poly(C)] and encephalomyocarditis virus were greatly enhanced by IFN-gamma pretreatment (priming) of wild-type cells or of mutant cells lacking an IFN-alpha/beta response; these include the primary induction of dsRNA-inducible mRNAs, including IFN-beta mRNA, and, to a lesser extent, the dsRNA-mediated activation of the p38 mitogen-activated protein (MAP) kinase(s). IFN-gamma priming of mRNA induction by dsRNA is dependent on JAK1 and shows biphasic kinetics, with an initial rapid (<30-min) response being followed by a more substantial effect on overnight incubation. The IFN-gamma-primed dsRNA responses appear to be subject to modulation through the p38, phosphatidylinositol 3-kinase, and ERK1/ERK2 MAP kinase pathways. It can be concluded that despite efficient priming of IFN-beta production, the IFN-alpha/beta pathways play no significant role in the primary IFN-gamma antiviral response in these cell-virus systems. The observed IFN-gamma priming of dsRNA responses, on the other hand, will likely play a significant role in combating virus infection in vivo.
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PMID:The antiviral response to gamma interferon. 1218 89

The therapy of chronic myeloid leukemia (CML), characterized by the presence of the Philadelphia chromosome in the clonal hematopoietic stem cells, has changed dramatically in the last year with the development of a specific inhibitor of the BCR-ABL tyrosine kinase. This medication, STI571 or imatinib, was recently approved by the Food and Drug Administration for CML patients refractory or intolerant to interferon. The medication has the potential to rapidly reverse the clinical and hematologic abnormalities of CML and is the paradigm of molecularly targeted therapy. STI571 is the first agent in Oncology that directly targets the molecular basis of a malignant disease, changing the way that we will treat these conditions in the future. This new field of molecular and cellular biology has the possibility of controlling not only malignant conditions but also diseases treated by other medical specialties.
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PMID:Signal transduction inhibitors (STI571): molecularly targeted therapy. 1224 10

Chronic myeloid leukemia shown to be associated with the Ph translocation,--characterised as a t(9;22)--, joins the bcr and abl genes and leads to expression of chimeric BCR-ABL protein with enhanced tyrosine kinase (TK) activity. This increased TK activity leads to malignant transformation by interference with the control of proliferation, cellular adherence and apoptosis. The presence of this protein in every CML cells is strong evidence of its pathogenetic role. Following this observations efforts were made to develop molecularly targeted therapies for CML. The specific inhibitor of BCR-ABL TK, STI571 was developed by Brian Druker and his co-workers in 1996. STI571 (Signal Transduction Inhibitor) occupies the kinase pocket of the BCR-ABL protein, and blocks ATP binding, thereby preventing phosphorylation of any substrate. Because of promising preclinical data STI571 entered clinical trials in 1998, using an oral formulation. The reports of this trials document excellent efficacy. Patients with chronic phase after failure with interferon therapy achieved more than 90% hematologic response, usually within 4-6 weeks, and 55% major cytogenetic response. Patients with advanced disease also responded, though less durably. In phase 2 studies the drug has continued to produce impressive results. STI571 has a very favourable pharmacologic feature, with high degree of specificity for its target, and therefore low toxicity for normal tissues, it is well tolerable, side effects were minimal. STI571 opens a new era in the treatment of malignancies, it is the first targeted molecular therapy which is able to target abnormal cells without damaging normal cells, compared with traditional antineoplastic drugs.
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PMID:[Tyrosine kinase inhibitor STI571: new possibility in the treatment of chronic myeloid leukemia]. 1244 Feb 60

Real-time RT-PCR has great advantages for estimating transcript levels in a variety of situations. These include relative rapid assay times (hours), reliability and ease of performing replicate analyses. In contrast, competitive PCR is a very labor-intensive procedure requiring a few days to generate useful data. We compared the same samples from CML patients by both methods. Importantly, we used the Bcr-Abl junction plasmid DNA, which is used as a competitor in the manual competitive PCR assay, to generate a standard curve for the real-time assay. This permitted reporting the real-time data as the number of BCR-ABL transcripts per microg of total RNA, which is the same format used for the competitive PCR assay. In this study, a total of 435 peripheral blood and marrow samples from 285 CML patients were analyzed by RT-PCR; these patients were undergoing therapy by STI-571, interferon, and bone marrow transplantation treatment. Most samples also had assay values for the Philadelphia chromosome (Ph), FISH and Western blotting for the Bcr-Abl oncoprotein. Our findings indicated that the real-time assay was less sensitive than the manual competitive RT-PCR assay (t = 5.118; P < 0.001). Of interest, the transcript levels in cell line mixtures with various ratios of K562/KG-1 (BCR-ABL positive/negative) cells were also significantly higher with the competitive RT-PCR assays than real-time RT-PCR, except for levels of BCR-ABL below 200 transcripts per microg of RNA. In both patient and cell line experiments, dividing the BCR-ABL transcripts by the total ABL transcripts virtually eliminated the difference between real-time BCR-ABL transcript values and quantitative competitive BCR-ABL transcript values, indicating that both BCR-ABL and ABL transcripts were underestimated by the real-time assay. In addition, the increased sensitivity of the nested, competitive RT-PCR was readily apparent in patients with minimal residual disease, which by the real-time were negative in the majority of patients but were positive by nested, competitive RT-PCR in 44.6% (n = 29) of samples analyzed (n = 65). These findings indicate that real-time RT-PCR, when normalized for the total ABL transcripts, can be used to monitor CML patients during therapy, but we suggest that nested, competitive RT-PCR be used to determine BCR-ABL/ABL transcript ratios at low transcript values or especially when real-time analyses are negative.
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PMID:Comparison of competitive-nested PCR and real-time PCR in detecting BCR-ABL fusion transcripts in chronic myeloid leukemia patients. 1467 51

Chronic myelogenous leukemia (CML) is a malignant disease resulting from the neoplastic transformation of a hematopoietic stem cell. Generation of the BCR-ABL fusion gene plays an essential role in causing the vast majority of CML. Clinical and laboratory studies have indicated that development of CML involves both the effects of BCR-ABL within its correct target cells and interactions of BCR-ABL target cells with the rest of the in vivo environment, and that the progression of the disease to blast crisis involves multiple genetic alterations. An efficient mouse bone marrow transduction and transplantation model for CML has recently been developed. This review summarizes the analysis of the roles of functional domains and downstream signaling pathways of BCR-ABL, of altered cytokine production, of interferon signaling pathways and of oncogene cooperation in the pathogenesis of CML using this murine model. The in vivo studies of leukemogenesis will help to advance mechanism-based therapies for CML, as well as to understand fundamental rules of leukemogenesis and hematopoiesis.
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PMID:The molecular mechanism of chronic myelogenous leukemia and its therapeutic implications: studies in a murine model. 1247 9

Imatinib mesylate (STI571, Gleevec, Glivec, a selective inhibitor of the BCR-ABL tyrosine kinase causative of chronic myeloid leukemia (CML), represents the paradigm of how a better understanding of the pathogenetic mechanisms of a neoplastic disease can lead to the development of a targeted molecular therapy. Phase II clinical trials have shown marked therapeutic activity of imatinib in all evolutive phases of CML, but notably in the chronic phase, where it induces complete hematological responses in almost 100% of patients resistant or intolerant to interferon, with a major cytogenetic response rate of 60%, including 41% complete cytogenetic responses. The preliminary results of an ongoing phase III multicenter randomized study comparing imatinib with interferon plus cytarabine as first-line treatment for CML favor imatinib in terms of efficacy and safety. If confirmed with longer follow-up,these results would establish imatinib as the choice therapy for the majority of CML patients, with allogeneic transplantation being restricted as initial therapy only to younger patients with a family donor. Longer follow-up will answer some questions, such as those on long-term safety, durability of the responses, whether these will translate into a survival prolongation and the possibility of molecular responses. In addition, further information on the mechanisms involved in the primary and acquired resistance to imatinib is needed. Besides the Bcr-Abl protein, the drug is also active against other tyrosine kinases, such as Abl, the stem-cell factor receptor (c-kit) and the platelet-derived growth factor receptor, whose inhibition might have potential implications for the treatment of several malignancies. In this sense, it must be pointed out that imatinib has shown a remarkable activity in gastrointestinal stromal tumors.
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PMID:Imatinib mesylate (Gleevec, Glivec): a new therapy for chronic myeloid leukemia and other malignancies. 1258 48

Indisputable advances in the conventional therapy of chronic myeloid leukemia (CML), like the establishment of interferon-alfa as the standard treatment for first chronic phase patients and the introduction of imatinib-mesylate as a highly active compound in patients failing interferon-alfa treatment or with more advanced disease are challenging allogeneic stem cell transplantation (SCT) as the single treatment modality, which currently offers long-term remissions below the threshold of sensitive molecular methods for the detection of BCR-ABL transcripts. Since stable molecular remissions are thought to be a prerequisite for cure of CML, allogeneic SCT remains the only curative treatment option for younger patients (i.e. beyond the age of 55 years), who have an HLA-matched related or unrelated donor. Nowadays, suitable HLA-matched unrelated donors can be identified for 70% to 75% of caucasian patients lacking an HLA-identical sibling donor, which substantially has promoted the broader application of allogeneic SCT.
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PMID:Allogeneic stem cell transplants in chronic myeloid leukemia. 1261 Oct 74


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