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:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It is well accepted that the Bcr-Abl oncoprotein encoded by the Philadelphia chromosome is responsible for causing chronic myelogenous leukemia (CML). We have previously demonstrated that expression of Bcr interferes with the oncogenic effects of Bcr-Abl. To examine the effects of increased Bcr expression on Bcr-Abl oncogenic effects in a more physiological system, we tested the leukemogenic potential of a clone of K562 cells (K6 K562) containing an inducible BCR gene in NOD/scid mice. In this clone, the BCR gene was placed under the control of a tetracycline (Tet) repression system with a cytomegalovirus (CMV) promoter. Induction of exogenous Bcr protein by removal of Tet from the culture medium caused a dramatic increase in Bcr serine kinase activity, yielding predominantly phosphoserine Bcr, despite the presence of Bcr-Abl in the kinase reaction mixture. Prior to induction, the endogenous Bcr was predominantly in the phosphotyrosine form because of phosphorylation by Bcr-Abl, which we previously have shown suppresses Bcr serine/threonine kinase activity. Injection of K6 K562 cells into NOD/scid mice under conditions where BCR expression was suppressed resulted in death or terminal illness in 100% of the mice within 35 days after injection. These mice had a severe wasting syndrome characterized by atrophy of bone marrow hematopoiesis, and/or neoplasia of liver, bone marrow and spleen. Neoplastic spleens from these mice usually contained b3a2 Bcr-Abl transcripts. In contrast, induction of BCR expression at the time of injection allowed 80% survival; these healthy mice had no detectable microscopic lesions in blood forming organs. This difference in survival was significant with P<0.0001. Of interest, mice that were fed Tet for 19 days to initiate the disease syndrome and then released from the BCR transcriptional block had a significantly better survival pattern than mice exposed to Tet throughout the entire period. Moreover, 30% of these mice (three mice) survived through day 50. We conclude from these findings that BCR gene expression strongly inhibits the oncogenic effects of Bcr-Abl in NOD/scid mice, yielding healthy mice in most cases.
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PMID:BCR gene expression blocks Bcr-Abl induced pathogenicity in a mouse model. 1131 35

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 BCR protein is involved in the inhibition of oncogenic activity of the Bcr-Abl oncoprotein. This inhibition is believed to be the result of binding to the SH2 domain of Bcr-Abl in a non-phosphotyrosine-dependent manner. We showed that the Arg to Leu mutation in the Phe-Leu-Val-Arg-Glu-Ser (FLVRES) sequence of the SH2 domain, known to interfere with phosphotyrosine sequence binding, did not block the binding of Bcr first exon sequences to the Abl SH2 domain. We examined the structural-functional properties of a first exon mutant of BCR lacking the oligomerization domain, termed Bcr(64-413), that encodes the Ser-Thr protein kinase activity of Bcr. The autokinase product contained a M(r) 45,000-47,000 and 55,000 protein. Both species were detected by a Bcr phosphoserine 354 sequence-specific antibody. In contrast, the S354A mutant of Bcr(64-413), although maintaining autokinase activity, produced only the M(r) 45,000-47,000 kinase product. Abl SH2 binding experiments indicated that the M(r) 55,000 species of Bcr(64-413) but not the M(r) 45,000-47,000 species bound strongly to glutathime transferase-Abl SH2. The S354A mutant of Bcr(64-413) did not bind to glutathime transferase-Abl SH2. An adenovirus encoding Bcr(64-413) S354A did not induce cell death in CML cell lines in contrast to wild-type Bcr(64-413). Our findings indicate that Ser-354 of Bcr is part of a gating mechanism, which, after its phosphorylation, allows structural changes to occur in the Bcr protein. This altered phosphoserine form of the Bcr protein selectively binds to the Abl SH2 domain of the oncoprotein, which we propose down-regulates the activity of the Bcr-Abl tyrosine kinase.
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PMID:Inhibition of the Bcr-Abl oncoprotein by Bcr requires phosphoserine 354. 1180 85

Surface-expressed BCR mediates the proliferation and expansion of antigen-specific B lymphocytes during a humoral immune response. Although several studies extensively characterize BCR proliferative signaling, the mechanisms linking these pathways to the cell cycle remain elusive. Using knockout mice, we show that c-Rel, a proto-oncogenic member of the NF-kappaB transcription factor family, is essential to BCR-mediated proliferation and cell cycle progression. Splenic B cells obtained from gene-targeted c-Rel knockout mice display a defective proliferation response to antigen receptor cross-linking, resulting in G(1) arrest. At the molecular level, we see that BCR stimulation of resting c-Rel(-/-) B cells fails to induce proper cyclin D3 and cyclin E expression, thereby negatively impacting G(1) phase cyclin-dependent kinase (CDK) activity. c-Rel-deficient B cells also exhibit incomplete phosphorylation of the Retinoblastoma protein (pRb) and poor expression of E2Fs, thus impeding the G(1) to S phase transition. Down-regulation of the pRb-related p130 protein during the G(0) to G(1) transition and removal of the CDK inhibitor p27(KIP1) in late G(1) parallel that of wild-type cells, suggesting that Rel-deficient B cells can exit the G(0) resting state and enter G(1) phase normally. Finally, we demonstrate that restoration of proliferation can be achieved partially upon reintroduction of cyclin E using a protein transduction method to reconstitute primary B cells. Collectively, these studies emphasize the importance of c-Rel in lymphocyte proliferation and oncogenesis, and highlight a requirement for c-Rel in establishing an effective humoral immune response.
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PMID:c-Rel regulation of the cell cycle in primary mouse B lymphocytes. 1214 27

Recent progress made in molecular biology, biotechnology, and genetics, especially in identifying, cloning, sequencing and characterization of normal and pathogenic genes, has led to the development of genetic therapy. Major efforts in the field can be summarized in two general approaches: gene therapy and antisense therapy. The second is to deliver to the target cells antisense molecules that target to mRNA with which they can hybridize and specifically inhibit the expression of pathogenic genes. Antisense oligonucleotides offer the possibility of specific, rational, genetic-based therapeutics. With encouraging results from preclinical and clinical studies of antisense oligonucleotides in the past decade, significant progress has been made in developing antisense therapy, with the first antisense drug now being approved for clinical use. In this article, we will discuss approaches to developing these drugs from preclinical to clinical settings. Of particular interest for the area of human cancer therapy, several cancer targets, including bcl-2, BCR-ABL, C-raf-1, Ha-ras, c-myc, PKC, PKA, p53 and MDM2, are reviewed as examples to illustrate the progress in this field and emphasize the importance of target selection and advanced antisense chemistry in the development of antisense therapy.
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PMID:Antisense anticancer oligonucleotide therapeutics. 1218 78

The Bcr-Abl fusion protein kinase causes chronic myeloid leukemia and is targeted by the signal transduction inhibitor STI-571/Gleevec/imatinib (STI-571). Sequencing of the BCR-ABL gene in patients who have relapsed after STI-571 chemotherapy has revealed a limited set of kinase domain mutations that mediate drug resistance. To obtain a more comprehensive survey of the amino acid substitutions that confer STI-571 resistance, we performed an in vitro screen of randomly mutagenized BCR-ABL and recovered all of the major mutations previously identified in patients and numerous others that illuminate novel mechanisms of acquired drug resistance. Structural modeling implies that a novel class of variants acts allosterically to destabilize the autoinhibited conformation of the ABL kinase to which STI-571 preferentially binds. This screening strategy is a paradigm applicable to a growing list of target-directed anti-cancer agents and provides a means of anticipating the drug-resistant amino acid substitutions that are likely to be clinically problematic.
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PMID:Mechanisms of autoinhibition and STI-571/imatinib resistance revealed by mutagenesis of BCR-ABL. 1265 40

STI-571 (imatinib, Gleevec, Glivec, CGP 57148) is an inhibitor of the Abl group of protein-tyrosine kinases. One of these enzymes, the Bcr-Abl oncoprotein, results from the fusion of the BCR and ABL genes that result from the reciprocal chromosomal translocation that forms the Philadelphia chromosome. The Philadelphia chromosome occurs in 95% of people with chronic myeloid leukemia. ABL is the cellular homologue of the oncogene found in murine Abelson leukemia virus, and BCR refers to breakpoint cluster region. The Bcr-Abl oncoprotein exhibits elevated protein-tyrosine kinase activity, which is strongly implicated in the mechanism of development of chronic myeloid leukemia. STI-571 is effective in the treatment of the stable phase of chronic myeloid leukemia. The c-Abl protein kinase domain exists in an active and inactive conformation. STI-571 binds only to the inactive state of the enzyme as shown by X-ray crystallography. The drug binds to a portion of the ATP-binding site and extends from there into adjacent hydrophobic regions. STI-571 is a competitive inhibitor of Abl kinase with respect to ATP. Resistance to STI-571 is often the result of mutations in residues of the Bcr-Abl kinase that ordinarily bind to the drug. Inhibition of target protein kinases represents an emerging therapeutic strategy for the treatment of cancer.
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PMID:STI-571: an anticancer protein-tyrosine kinase inhibitor. 1367 30

Imatinib mesylate (STI571), a specific inhibitor of the BCR-ABL tyrosine kinase, exhibits potent antileukemic effects in vitro and in vivo. Despite the well established role of STI571 in the treatment of chronic myelogenous leukemia, the precise mechanisms by which inhibition of BCR-ABL tyrosine kinase activity results in generation of antileukemic responses remain unknown. In the present study we provide evidence that treatment of CML-derived BCR-ABL-expressing leukemia cells with STI571 results in activation of the p38 mitogen-activated protein (MAP) kinase signaling pathway. Our data indicate that STI571 induces phosphorylation of the p38 and activation of its kinase domain, in KT-1 cells and other BCR-ABL-expressing cell lines. We also identify the kinases MAP kinase-activated protein kinase-2 and Msk1 as two downstream effectors of p38, activated during inhibition of BCR-ABL activity by STI571. Importantly, pharmacological inhibition of p38 reverses the growth inhibitory effects of STI571 on primary leukemic colony-forming unit granulocyte/macrophage progenitors from patients with CML. Altogether, our data establish that activation of the p38 MAP kinase signaling cascade plays an important role in the generation of the effects of STI571 on BCR-ABL-expressing cells. They also suggest that, in addition to activation of mitogenic pathways, BCR-ABL promotes leukemogenesis by suppressing the function of growth inhibitory signaling cascades.
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PMID:Role of the p38 mitogen-activated protein kinase pathway in the generation of the effects of imatinib mesylate (STI571) in BCR-ABL-expressing cells. 1505 60

Chronic myelogenous leukaemia (CML) cells show expression of BCL-X(L), an anti-apoptotic oncogene. This expression is induced by BCR-ABL protein kinase through activation of the signal transducer and activator of transcription-5 protein (STAT5). To date, however, the contribution of BCL-X(L) and STAT5 to the transforming phenotype in CML is still unclear. This study was aimed at defining the status of activated STAT5 and BCL-X(L) expression and their relation to BCR-ABL rearrangement in CML cells derived from patients at different clinical stages. Twenty-seven consecutive patients with CML were enrolled in the study. Peripheral blood mononuclear cells were lysed and subjected to immunoprecipitation and Western blotting to analyse phosphorylated STAT5. The p210 BCR-ABL rearrangements were determined by reverse transcriptase-polymerase chain reaction (RT-PCR) and BCL-X(L) expression by semi-quantitative RT-PCR. We found that increased transcription of BCL-X(L) gene was associated with phosphorylated STAT5 in the majority of blast crisis patients and in a few accelerated and chronic phase patients. Moreover, BCL-X(L) expression levels were found to be decreased in chronic phase, contrary to a marked increase in blast crisis. We found no difference in expression of BCL-X(L) and phosphorylated STAT5 when related with b3a2 and b2a2 BCR-ABL rearrangements. These results suggest that STAT5 activity and BCL-X(L) overexpression may reflect a stage of differentiation among CML phases, and this could contribute to BCR-ABL-dependent transformation.
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PMID:Differences in BCL-X(L) expression and STAT5 phosphorylation in chronic myeloid leukaemia patients. 1508 59

Chronic myeloid leukemia (CML) is a stem cell disorder caused by a constitutively activated tyrosine kinase, the Bcr-Abl oncoprotein. An inhibitor of this tyrosine kinase, imatinib mesylate, is rapidly becoming the first-line therapy for CML. However, the development of resistance to this drug is a frequent setback, particularly in patients in advanced phases of the disease. Several mechanisms of resistance have been described, the most frequent of which are amplification and/or mutations of the BCR-ABL gene. To overcome resistance, several approaches have been studied in vitro and in vivo. They include dose escalation of imatinib, combination of imatinib with chemotherapeutic drugs, alternative Bcr-Abl inhibitors, inhibitors of kinases downstream of Bcr-Abl, farnesyl and geranylgeranyl transferase inhibitors, histone deacetylase, proteasome and cyclin-dependent kinase inhibitors, arsenic trioxide, hypomethylating agents, troxacitabine, targeting Bcr-Abl messenger RNA, and immunomodulatory strategies. It is important to understand that these approaches differ in efficiency, which is often dependent on the mechanisms of resistance. Further investigations into the molecular mechanisms of disease and how to specifically target the abnormal processes will guide the design of new treatment modalities in future clinical trials.
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PMID:Biology of chronic myeloid leukemia and possible therapeutic approaches to imatinib-resistant disease. 1523 91


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