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)

The BCR/ABL oncogene in chronic myelogenous leukemia produces an activated tyrosine kinase fusion protein (p210). Like other tyrosine kinase oncogenes, BCR/ABL can abrogate the interleukin-3 (IL-3) dependence of lymphoid cell lines. To investigate the ability of BCR/ABL to generate growth factor independence in myeloid cells, the IL-3 dependent myeloid cell line NFS/N1.H7 (H7) was transfected with the p210BCR/ABL-containing plasmid, pGD210. Stable clones A54 and A74 were capable of IL-3 independent growth and tumor formation in syngeneic mice. Relief of growth factor dependence was not mediated by autocrine release of IL-3. The baseline proliferation rate of the BCR/ABL transformed cells was greater than that of the parental H7 cells maximally stimulated by IL-3. Abundant constitutive expression of c-myc, c-jun, and c-fos was observed in the p210BCR/ABL transfectants even in low serum conditions. In contrast, c-myc expression in H7 cells was dependent upon IL-3 stimulation, and neither c-jun nor c-fos was highly expressed following IL-3 stimulation in H7 cells. Thus, BCR/ABL transformation and relief of IL-3 dependence involve not only pathways that can substitute for IL-3 induced growth via tyrosine kinase mediated signals, but also pathways that recruit constitutive c-jun and c-fos expression.
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PMID:BCR/ABL confers growth factor independence upon a murine myeloid cell line. 137 13

Chromosome Philadelphia (Ph) which originated from translocation 9;22 is an aberration connected with chronic myelogenous leukaemia (CML) and with part of the cases of acute lymphoblastic leukaemia (ALL). The analysis on the molecular level has shown that the rearrangement of ABL and BCR genes is the most important consequence of this translocation. The new hybrid gene translates the protein p210, which shows tyrosine phosphokinase activity. This protein could play an important role in the pathogenesis of CML. The investigations of BCR/ABL rearrangement on molecular level are an important tool for differential diagnosis of lymphoblastic crisis of CML and ALL and also are very valuable in detection of residual Ph positive cells in cytogenetic conversion of CML.
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PMID:[Molecular biology of chronic myeloid leukemia]. 148 67

The translocation between chromosome 9 and chromosome 22 which creates the Philadelphia chromosome moves the ABL oncogene from its normal location on chromosome 9 and fuses it with a portion of the BCR gene on chromosome 22. This new BCR/ABL fusion gene generates a unique 8.7 kilobase (kb) RNA which codes for a new 210 kilodalton (kd, p210) protein which has a protein tyrosine kinase activity that is greatly increased in comparison to the normal ABL protein. The human K562 cell line was derived from a patient with CML, and serves as one model for the regulation of expression of the ABL and BCR/ABL genes. This study examines the expression of the BCR/ABL fusion gene and the normal ABL gene in relation to differentiation and changes in proliferative state. The expression of both the normal ABL transcripts and the BCR/ABL fusion transcript decrease approximately ten-fold when the cells are induced to differentiate with hemin. In contrast, expression of the MYC oncogene is unaffected by hemin-induced differentiation. The results suggest that both ABL and BCR/ABL expression vary in proportion to the differentiation of the cells, but minimally if at all as a function of the cells' proliferative state.
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PMID:ABL oncogene expression during erythroleukemia cell differentiation. 199 45

The presence of Philadelphia chromosome t(9:22) is a hallmark of 95% of clinical cases of chronic myelogenous leukemia (CML) as well as 20% of adult acute lymphoblastic leukemia (ALL) and 5% of acute myeloid leukemia (AML). The product of t(9;22) is a fusion protein BCR-ABL. The fusion proteins of CML, ALL and AML have increased tyrosine kinase activity and show a transforming potential in vitro and in animal models. The shorter p190 protein is associated almost only with ALL and AML, while the protein p210 is present in both chronic phase and blast crisis of CML and also in 50% of Philadelphia-positive (Ph1+) ALL. In CML the transition from chronic phase to blast crisis is usually accompanied by additional genetic events, e.g. additional chromosomal abnormalities, and oncogene activation(s). The detailed understanding of molecular basis of CML, and Ph1+ ALL and AML provides highly sensitive molecular and serological methods to complement classical cytogenetics. The advantages and limitations of these techniques are described and discussed below.
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PMID:Molecular pathology of chronic myelogenous leukemia. 224 53

A patient with a chronic myeloproliferative disease associated with a 100% t(5;12) translocation was treated with 3 million U per day of IFN-alpha 2a. Besides being consistently Ph-negative, the search for BCR/ABL hybrid transcripts by means of RT-PCR was also negative. Total cytogenetic conversion to diploid hematopoiesis was obtained, but after discontinuation of IFN a 50% relapse of t(5;21) mitoses was found, and treatment was resumed. There is some degree of consensus that the mechanism by which IFN-alpha suppresses the Ph+ clone in CML consists in the restoration of normal adhesion of CML progenitors to the marrow stroma, by preventing transcription of the BCR/ABL mRNA, and hence expression of the p210 tyrosine kinase. However, if the 'faulty adhesion' hypothesis, and its correction by IFN-alpha, is to be considered correct, this case proves that it must include also Ph-negative, not BCR-ABL rearranged clonal myeloid proliferations.
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PMID:Chronic clonal myeloproliferative disease associated with a t(5;21) translocation. Complete but transient hematologic and cytogenetic remission induced by interferon-alpha. 759 88

Sequence specificity of inhibitory effects of various BCR-ABL anti-sense oligodeoxynucleoside phosphorothioates (AS PS-ODN) on the proliferation of the chronic myeloid-leukemia cell line BV173 was examined. We confirmed that 26, 18, and 16mer B2A2 AS PS-ODN had strong inhibitory effects on the proliferation of BV173 cells with B2A2 mRNA expression, and that B3A2 AS PS-ODN were equally inhibitory when cultures were initiated at lower cell concentrations. However, at higher cell concentrations, the inhibitory effects by B3A2 AS PS-ODN were reduced and B2A2 AS PS-ODNs could suppress the proliferation of BV173 cells with much more relative sequence specificity. The 26mer B2A2 AS PS-ODN induced apoptosis of BV173 cells following reduction of BCR-ABL mRNA expression and p210 protein synthesis. Various sense (S), reverse order, and random sequences had no inhibitory effects except 16mer B2A2 S and B3A2 S that revealed significant suppressive effects. Furthermore, 26mer B3A2 AS also reduced B2A2 mRNA expression and p210 protein synthesis, while 16mer S sequences did not. These results suggest that B2A2 AS may be cross-reactive with B3A2 AS on the growth suppression of CML cells under certain culture conditions, possibly due to their partial hybridization to the ABL portion of the target mRNA, although other non-sequence-specific mechanisms are also possible.
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PMID:Sequence specificity on the growth suppression and induction of apoptosis of chronic myeloid leukemia cells by BCR-ABL anti-sense oligodeoxynucleoside phosphorothioates. 760 69

Experiments were performed to elucidate the mechanism through which p210 BCR-ABL, by its downstream signals, regulates c-myc messenger RNA expression in hematopoietic cells. We studied a model system in which stable expression of p210 BCR-ABL in interleukin-3 (IL-3) dependent murine myeloid cell lines led to growth factor independent transformation. Active c-myc transcription was observed in p210 BCR-ABL transformed cells by nuclear run-on assay, and in heterologous reporter assays performed with the 5' regulatory region of murine c-myc linked to firefly luciferase. Transcription initiation occurred primarily from the P2 promoter in p210 BCR-ABL transformed cells. Cis and trans elements responsible for transcription initiation from the c-myc P2 promoter were studied. Expression of E2F1 protein in p210 BCR-ABL transformed cells accounted, in part, for binding to the E2F site of the P2 c-myc promoter. The functional importance of E2F1 expression in p210 BCR-ABL transformed cells toward c-myc transcription was established in reporter assays performed with the P2 c-myc promoter containing either wild-type or mutant E2F sites. Mutation of the E2F motif of P2 5' c-myc reduced activity of the promoter by 50%. By gel mobility shift, E2F1 was found in P2 c-myc band shift complexes along with the cyclin-dependent kinase 2. Therefore, coupling of E2F to components of the retinoblastoma-cyclin pathway defines a route from p210 BCR-ABL to c-myc transcription, which is required for p210 BCR-ABL transformation.
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PMID:Role for E2F1 in p210 BCR-ABL downstream regulation of c-myc transcription initiation. Studies in murine myeloid cells. 765 19

The Philadelphia (Ph) chromosome is detected in leukaemia cells in approximately 20% of adults with acute lymphoblastic leukaemia (ALL). When treated with chemotherapy alone, Ph-positive ALL has a poor prognosis, and patients may benefit from bone marrow transplantation in first remission. Here we report a patient with chromosomally normal bone marrow, in all 60 cells analysed, who was found to have the p210-type BCR-ABL chimaeric transcript by RT/PCR. Fluorescence in situ hybridization was labelled cosmid probes for BCR and ABL showed the presence of BCR-ABL juxtaposition on a normal chromosome 22 in leukaemia cell metaphases. We conclude that molecular and cytogenetic methods should be used in conjunction to detect the BCR-ABL gene rearrangement in ALL.
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PMID:Detection of the BCR-ABL gene by reverse transcription/polymerase chain reaction and fluorescence in situ hybridization in a patient with Philadelphia chromosome negative acute lymphoblastic leukaemia. 778 93

The Philadelphia translocation commonly observed in chronic myeloid leukaemia (CML) and a proportion of cases of acute leukaemia results in the creation of a chimeric fusion protein, BCR-ABL. The fusion protein exhibits an elevated tyrosine kinase activity as compared to normal ABL. Using a temperature sensitive mutant of p210 BCR-ABL (ts-p210) we find that the primary effect of BCR-ABL expression in an IL-3 dependent cell line is to prolong survival following growth factor withdrawal; only a small proportion of cells remain viable and rapidly evolve to complete growth factor independence. During passage in the presence of IL-3 at the temperature permissive for kinase activity, ts-p210 expressing cultures become dominated by completely growth factor independent cells within 10-30 days. There is also a significant difference between BCR-ABL and IL-3 mediated signalling with respect to the MAP kinase pathway; in contrast to IL-3 stimulation or v-ABL expression, BCR-ABL does not signal ERK 2 (MAP 2 kinase) activation, underlining the apparent inability of BCR-ABL to deliver an immediate proliferative signal in Ba/F3 cells. Our data suggest that growth factor independence does not simply reflect the convergence of BCR-ABL and IL-3 mediated signalling pathways and its development, at least in Ba/F3 cells, requires prolonged exposure to BCR-ABL kinase activity. We suggest that the myeloid expansion characteristic of CML may result from the prolongation of survival of myeloid progenitor cells under conditions of limiting growth factor rather than their uncontrolled proliferation.
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PMID:A temperature sensitive p210 BCR-ABL mutant defines the primary consequences of BCR-ABL tyrosine kinase expression in growth factor dependent cells. 781 29

The detection of BCR-ABL transcripts by polymerase chain reaction and hybridization protection assay was investigated in 59 adults with acute leukemia in whom the Philadelphia chromosome (Ph) abnormality was not documented by cytogenetic analysis. These included 35 patients with acute lymphocytic leukemia (ALL) and 24 with acute myelogenous leukemia (AML). Overall, three patients were found to have Ph-related molecular abnormalities; one had p190 and two had p210 disease. All three patients had ALL and were among 16 patients with insufficient metaphases by cytogenetic analysis, yielding an incidence of 19% in the latter category. Based on a 32% incidence of insufficient metaphases in our adult ALL population, we project an additional detection rate of 6% Ph-positive ALL by molecular studies and an overall incidence of 20% (14% + 6%) Ph-positive or BCR-ABL-positive ALL. None of the remaining patients with ALL and none of the 24 patients with AML investigated had BCR-ABL-positive disease. We conclude that molecular studies are useful in detecting BCR-ABL-positive disease in a subset of patients with Ph-positive ALL who are not identified by cytogenetic analysis because of insufficient metaphases.
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PMID:What is the contribution of molecular studies to the diagnosis of BCR-ABL-positive disease in adult acute leukemia? 810 97


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