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)

Retinoic acid receptor-beta (RAR beta) and signal transducer and activator of transcription 1 (STAT1) are important mediators of the antiproliferative and apoptotic actions of retinoids and cytokines/growth factors, respectively. Expression of both RAR beta and STAT1 is lost in most breast cancer cell lines but it can be induced by retinoids in estrogen receptor-positive cells. We investigated a possible functional connection between these two mediators and present evidence supporting RAR beta as a tumor suppressor. First, by using different receptor-selective retinoids, we demonstrated that RAR beta induction in MCF-7 cells by all-trans-retinoic acid (atRA) was associated with the activation of STAT1 gene transcription. The direct involvement of RAR beta in atRA-induced STAT1 gene activation was further demonstrated by showing that transfection with an anti-sense RAR beta construct blocked atRA-induced STAT1 expression in MCF-7 cells whereas introduction of a sense-RAR beta construct resulted in STAT1 induction by atRA in MDA-MB 231 cells. In addition, we showed that STAT1 was phosphorylated/activated under atRA treatment of MCF-7 cells; this process required the involvement of RAR beta and protein synthesis. STAT1 phosphorylation/activation was accompanied by increased tyrosine kinase activity that was not due to the activation of JAK1, JAK2 or Tyk 2, suggesting the possible involvement of an unidentified tyrosine kinase.
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PMID:The induction and activation of STAT1 by all-trans-retinoic acid are mediated by RAR beta signaling pathways in breast cancer cells. 1059 80

The ETV6/TEL gene has been reported to fuse to PDGFRbetab MDS1/EVI1, BTL, ACS2, STL, JAK2, ABL, CDX2, TRKC, AML1, and MN1. Among them, PDGFRbeta, ABL, JAK2, and TRKC are tyrosine kinases (TK). We identified a novel ETV6 partner gene, ARG (ABL-related gene or ABL2), another TK gene in a cell line established from a patient with acute myelogenous leukemia (AML-M3) with a t(15;17)(q22;q11.2) and a t(1;12)(q25;p13), which has the remarkable feature to differentiate to mature eosinophils in culture with all-trans retinoic acid and cytokines. The ETV6/ARG transcripts consisted of exon 1 to 5 of ETV6 and the 3' portion of ARG starting from exon 1B or exon 2, resulting in an open reading frame for a fusion protein consisting of the entire PNT oligomerization domain of ETV6 and all of the functional domains of ARG including the TK domain. This is the same protein structure as identified in the other ETV6 TK fusion proteins. The reciprocal ARG/ETV6 transcript was not expressed, and the normal ETV6 allele was not deleted or rearranged. Although the ABL is known to be involved in various human malignancies, ARG has not been involved in human malignancies despite its high homology to ABL. Thus, this is the first report showing involvement of ARG in human leukemia. The ETV6/ARG protein may be involved in the unique differentiation capacity of this cell line. (Blood. 2000;95:2126-2131)
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PMID:A new ETV6/TEL partner gene, ARG (ABL-related gene or ABL2), identified in an AML-M3 cell line with a t(1;12)(q25;p13) translocation. 1070 84

Chronic myeloid leukemia (CML) is a hematological malignancy resulting from clonal expansion and massive accumulation of leukemic myeloid cells that retain differentiation and maturation capacity. Since CML cell accumulation has been related to apoptosis inhibition by the product of the BCR-ABL gene, attempts to eradicate leukemic cells would require therapeutic drugs able to overcome this inherent resistance. Here, we investigated in vitro the apoptotic effect of all-trans retinoic acid (ATRA) and cytosine arabinoside (ARA-C), employed alone, in combination or in sequence, on freshly isolated cells from 10 patients with chronic-phase CML. Our cell cultures showed that both ATRA and ARA-C were able to induce apoptosis in CML cells, even if ARA-C resulted more effective than ATRA. The combined use of ATRA and ARA-C seemed to have only an additive effect while the sequential use did not show any advantage. These in vitro observations indicate that ATRA and ARA-C may be effective in reducing CML cells through apoptosis induction, suggesting that it could be worthwhile to examine ATRA and ARA-C combinations in the therapy of CML.
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PMID:In vitro apoptotic response of freshly isolated chronic myeloid leukemia cells to all-trans retinoic acid and cytosine arabinoside. 1115 76

Our previous report demonstrated that all-trans-retinoic acid (ATRA) induces detachment and death under serum starvation in several human tumor cell lines. In this study, we examined the influence of cell-extracellular matrix interaction on the ability of ATRA to induce apoptosis. Plating of human hepatoma Hep3B cells onto poly-hydroxyethylmethacrylate-coated plates in the absence of serum resulted in the acceleration of ATRA-induced apoptosis. In contrast, ATRA-induced apoptosis was significantly suppressed by plating cells onto Matrigel-coated plates but not suppressed by culturing onto collagen-, laminin-, vitronectin-, or fibronectin-coated plates. Exogenously added soluble collagen, laminin, fibronectin, vitronectin or Matrigel failed to suppress ATRA-induced apoptosis. Results from the adhesion assay indicated that the cell attachment to fibronectin was significantly inhibited by ATRA. Treatment with perturbing antibody against integrin alpha5 or beta1 subunits resulted in promotion of ATRA-induced apoptosis. Moreover, the proteolytic cleavage of alpha5beta1 integrin and focal adhesion kinase (FAK) proteins is linked to the early phase of the ATRA-induced apoptotic process. Furthermore, ATRA-induced detachment, death, and cleavage of alpha5beta1 integrin and FAK were drastically suppressed by plating cells onto Matrigel-coated plates. These findings provide evidence that abrogation of cell adhesion, through proteolysis of alpha5beta1 integrin and FAK, is closely linked to ATRA-induced apoptosis in Hep3B cells.
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PMID:Proteolysis of integrin alpha5 and beta1 subunits involved in retinoic acid-induced apoptosis in human hepatoma Hep3B cells. 1136 41

All-trans retinoic acid (ATRA), alone or combined with chemotherapy (CHT) is widely used to induce complete remission (CR) in newly diagnosed acute promyelocytic leukemia (APL). If used alone, ATRA results in a substantial proportion of CRs. To maintain remission further, ATRA is commonly used with cycles of CHT, frequently followed by autologous (auto) or allogeneic (allo) stem cell transplantation (SCT), as early reports have shown that the continuous administration of ATRA as single therapy almost invariably leads to relapse in a short period of time (months). Pharmacokinetic studies have shown that induced resistance to ATRA is frequently suppressed by the intermittent use of the drug. In this study we applied an intermittent therapeutic protocol with ATRA in five APL patients who were either molecularly refractory after combined ATRA/CHT treatment, or relapsed, or at diagnosis, but not eligible for the combination treatment because of previous toxicity. They were treated with ATRA (45 mg/m2/day) for 21 days. The treatment was then prolonged continuously for 1 week every 2 weeks. Molecular analysis was performed by qualitative and quantitative reverse transcription-polymerase chain reaction (RT-PCR). All patients obtained molecular remission, as assessed by qualitative RT-PCR, in a median of 3 months (range 1-15). Quantitative RT-PCR confirmed these data, showing a progressive reduction (1 or 2 logs) to a 'negligible quantity' of PML-RARalpha fusion transcript (ratio PML-RARalpha/ABL x 10(4) ABL < 10(-1)) in all but one patient treated with pulsed ATRA therapy. These data were confirmed with qualitative and quantitative RT-PCR. After a median follow-up of 17 months from the start of ATRA therapy, 4/5 patients (80%) are in continuous complete molecular remission. To our knowledge, this is the first clinical observation that intermittent ATRA therapy (without chemotherapy) is effective not only in inducing but also in maintaining long-term molecular remission in APL patients. This approach could therefore be effective, if confirmed in larger series, in relapsed/refractory patients unsuitable for high-dose therapy and SCT; it may be proposed as induction therapy for selected older APL patients if considered not to be eligible for combined ATRA/CHT due to inadequate performance status or concurrent disease.
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PMID:Pulsed ATRA as single therapy restores long-term remission in PML-RARalpha-positive acute promyelocytic leukemia patients: real time quantification of minimal residual disease. A pilot study. 1168 9

The accuracy of cytogenetic diagnosis in the management of hematological malignancies has improved significantly over the past 10 years. Fluorescence in situ hybridization (FISH), a technique of molecular cytogenetics, has played a pivotal role in the detection of unique sub-microscopic chromosomal rearrangements that helped in the identification of chromosomal loci, which contain genes involved in leukemogenesis. We studied the feasibility and sensitivity of the FISH technique for molecular analysis of translocations markers, t(9;22) and t(15;17) for accurate molecular diagnosis and for monitoring the disease in 21 patients with chronic myeloid leukemia (CML) who received interferon-alpha and/or chemotherapy (7 patients), bone marrow transplantation (14 patients), and 14 patients with acute promyelocytic leukemia (APL) who received all-trans-retinoic acid (ATRA) and/or chemotherapy. We also applied conventional karyotyping (CK) for identification of t(9;22) and t(15;17) at diagnosis. All CML cases had a Ph; t(9;22) and except for two cases all APL had t(15;17). The FISH studies on CML marrows in complete cytogenetic remission (CCR) (100% Ph- by CK) achieved by IFN-alpha, showed 0-2.5% of cells with BCR-ABL fusion in first cytogenetic remission (Controls, range 0.5-1.5%). Repeat follow-up FISH studies could be done in two cases in remission, which demonstrated 0-10% of cells with BCR-ABL fusion. Evaluation of Ph positive status of CML marrow at diagnosis by CK (100% Ph+ cells) and FISH (80-92% BCR-ABL fusion) pointed the existence of dormant clone of normal residual hematopoietic cells along with actively proliferating clones of Ph positive cells. Fluorescence in situ hybridization analysis of post-BMT CML marrows in CCR (0% Ph+ mitoses) could detect MRD with range of 1-6%. Among 14 patients, 9 who showed percentage of BCR-ABL positive cells (0.0-1.5%) almost similar to normal controls, 6 patients had comparatively good prognosis (disease-free survival 7-14 months). Of five patients with residual leukemic cells in the range of 2-6%, 4 relapsed within a period of 3-24 months. Fourteen APL patients in CCR [100% t(15;17) negative cells by CK] were evaluated by FISH to check the presence of residual leukemic cells. In these patients FISH could efficiently detect 1-14.5% of residual cells with PML-RARA (patients mean MRD 5%, controls mean MRD 3.5%, P=.02). Since the time of FISH analysis, 5 to 7 patients with higher fraction of leukemic cells (5-11%) relapsed within a short period (1-7 months). On the contrary, 5 of 7 patients with either absence or low percentage of PML-RARA positive cells remained in complete remission for 11-24 months. Our data show that FISH has a potential to detect and measure the fraction of aberrant malignant cells in remission marrows, induced by BMT in CML and chemotherapy in APL. These findings encourage the investigations on a large scale to merit its potential for identification of patients at high risk. In the present studies, FISH on interphase cells also demonstrated its efficiency in the molecular diagnosis by its ability to detect BCR-ABL and PML-RARA fusion in CML with masked/variant Ph and t(15;17) negative APL, respectively. The efficiency of technique in molecular diagnosis was also proved in one of the CML patients who progressed to myeloid blastic phase where interphase FISH could identify an extra BCR-ABL fusion on both chromosomes 9 indicating insertion of BCR into ABL and its duplication.
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PMID:Fluorescence in situ hybridization: a highly efficient technique of molecular diagnosis and predication for disease course in patients with myeloid leukemias. 1175 52

The function of the lung is dependent upon differentiation and proliferation of respiratory epithelial cells and the synthesis/secretion of surfactant lipids and proteins into air space. During the respiratory inflammatory response, cytokines produced by macrophages and epithelial cells in the respiratory system have significant influence on surfactant protein homeostasis. We report here that among family members of Janus family tyrosine kinase (JAK) and signal transducers and activators of transcription (STAT), only JAK 1 and STAT3 stimulated the -500 to +41 promoter activity of the surfactant protein B (SP-B) gene in respiratory epithelial cells. JAK1 and STAT3 were co-localized in alveolar type II epithelial cells where SP-B is synthesized and secreted. Interleukin 6 and interleukin 11, known to activate STAT3 synergistically, stimulated the SP-B promoter activity with retinoic acid, which is at least partially mediated through interactions between STAT3 and retinoid nuclear receptor enhanceosome proteins in pulmonary epithelial cells.
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PMID:Transcriptional stimulation of the surfactant protein B gene by STAT3 in respiratory epithelial cells. 1178 90

The lining of the trachea consists of a pseudostratified, mucociliary epithelium that under a variety of conditions, such as vitamin A deficiency, toxic and mechanical injury, becomes a stratified squamous epithelium. Several in vitro cell culture models have been established to study the process of differentiation of airway epithelium. Such studies have indicated that mucosecretory differentiation of tracheal epithelial cells can be modulated by substratum. This study was undertaken to understand molecular mechanisms of squamous differentiation in tracheal epithelia. Primary cultured tracheal cells grown on uncoated filters were differentiated to single layer of squamous cells, whereas cells were grown as stratified columnar cells on collagen-I coated filters. The responses to secretagogues were altered according to culture conditions. DD-PCR revealed that FAK and a WD protein expression was increased in squamous tracheal epithelia. Expression of a WD protein was changed by the treatment of retinoic acid in various epithelial cells. These results indicated that squamous differentiation of tracheal cells changes the expression of a variety of genes, and that the experimental model for this study can be employed to study molecular mechanisms of squamous differentiation in airway epithelial cells.
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PMID:Differential expression of a WD protein during squamous differentiation of tracheal epithelial cells. 1211 30

Significant advances have been made in the development of targeted interventions for hematologic malignancies. Progress has been made in defining the molecular pathogenesis of human leukemias. Data indicate that nonrandom, somatically acquired translocations, inversions, and other abnormalities occur in many acute leukemias. In the treatment of acute promyelocytic leukemia (APL), targeted therapy with all-trans retinoic acid (ATRA) and anthracycline-based chemotherapy leads to dramatic improvements in disease-free survival. Imatinib mesylate, a signal transduction inhibitor that inhibits tyrosine kinase activity, the protein product of the ABL proto-oncogene, has remarkable activity in patients with chronic myeloid leukemia (CML) and Philadelphia chromosome-positive (Ph(+)) acute lymphoblastic leukemia (ALL). Farnesyltransferase inhibitors (FTIs), a promising class of agents that target multiple pathways including Ras proteins, are potential anticancer therapy for a wide range of malignancies, including leukemias and myelodysplastic syndromes (MDS). There also is evidence that recombinant human erythropoietin therapy (r-HuEPO) can benefit patients with chronic lymphocytic leukemia (CLL), multiple myeloma, and lymphomas. This supplement will discuss advances in our understanding of human leukemias, including the use of unconjugated monoclonal antibodies such as Campath-1H (Wellcome, Beckenham, UK, and Ilex Oncology, San Antonio, TX) and rituximab and immunoconjugates such as gemtuzumab ozogamicin and BL-22. Although these novel therapies are beginning to fulfill their promise, continued research efforts are needed to determine the optimal role of targeted therapy in acute and chronic leukemias.
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PMID:Advancing the treatment of hematologic malignancies through the development of targeted interventions. 1244 45

Molecular targeting therapies for hematological malignant diseases such as monoclonal antibodies and small molecules have been reviewed. Imatinib mesylate (STI571) targets the tyrosine kinase activity of the BCR-ABL fusion protein in CML, and was superior to IFN-alpha plus low-dose cytarabine in newly diagnosed chronic-phase CML in a phase III randomized study. Imatinib induced apoptosis in BCR-ABL-positive cells in vitro, and activates several signaling pathways such as PI3K/Akt, STAT5 and Ras/MAPK. Combination therapies with imatinib and new strategies for downregulation of intracellular BCR-ABL protein levels have also been investigated from the phenomenon of resistance to imatinib. Anti-CD20 (rituximab) became the first monoclonal antibody approved for the treatment of a relapsed/refractory follicular/low-grade NHL and promising results were obtained from a phase III randomized study. Although antibody-dependent cell-mediated cytotoxicity and complement-mediated cytotoxicity are likely to be the major effectors of B-cell depletion in vivo, direct cytotoxicity by CD20 monoclonal antibody on B-cell lines in vitro has been reported. Anti-CD33 (Mylotarg) and FLT3 inhibitors for AML have also been used in clinical trials and signaling pathways induced by these agents are under intensive investigation. Arsenic trioxide, like all-TRANS-retinoic acid (ATRA), downregulates promyelocytic leukemia protein/retinoic acid receptor-alpha (PML/RARalpha) fusion protein and induced apoptosis in APL cells, and promising results were obtained from ATRA-resistant APL patients. Finally we show our promising in vitro and in vivo data of R-etodolac (a non-steroidal anti-inflammatory drug lacking cyclooxygenase inhibitor activity) against chronic lymphocytic leukemia (CLL) cells.
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PMID:Apoptosis induced by molecular targeting therapy in hematological malignancies. 1464 49


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