Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chronic myelogenous leukemia (CML) is associated with the reciprocal translocation of a region of chromosome 22 called BCR with the c-abl gene of chromosome 9.5' coding sequences from the BCR gene are spliced in-frame to the second exon of the ABL gene to produce a CML-specific 8.5 kilobase message which encodes the BCR-ABL hybrid protein P210. To definitively identify and characterize the normal BCR gene product, sequences from BCR cDNA clones were used to reconstitute the coding portion of the normal message in retroviral and bacterial transcription vectors. The normal BCR gene product was demonstrated to be a phosphoprotein of 160 kilodaltons by in vitro translation and immunoprecipitation from lysates of NIH3T3 lines expressing BCR retroviruses. Whereas BCR-homologous RNA levels in these cell lines were increased 50 fold, BCR protein levels increased only 2 to 10 fold depending on the presence or absence of BCR-specific 5' and 3' untranslated regions. We observe a kinase activity associated with this protein but we do not observe morphological transformation of NIH3T3 cells as a result of its overproduction.
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PMID:Structural characterization of the BCR gene product. 265 72

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

Genes encoding c-ABL kinase and BCR protein are targeted by yet-unknown mechanisms causing DNA double-strand breaks resulting in the generation of a chimeric gene encoding BCR/ABL fusion tyrosine kinase. BCR/ABL kinase displays transforming activity because of its constitutive kinase activity causing deregulated proliferation, apoptosis, differentiation, and adhesion. Moreover, BCR/ABL kinase is able to facilitate DNA repair, prolong activation of G2/M and S cell cycle checkpoints, and elevate expression of the antiapoptotic protein Bcl-X(L), making malignant cells less responsive to antitumor treatment. BCR/ABL may also stimulate generation of reactive oxygen species and enhance spontaneous DNA damage in tumor cells. Unfortunately, BCR/ABL kinase compromises the fidelity of DNA repair mechanisms, thus contributing to the accumulation of additional genetic abnormalities that lead to resistance to inhibitors such as imatinib mesylate and to malignant progression of the disease. Therefore, chronic myelogenous leukemia cells display mutator phenotype.
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PMID:Genomic instability: The cause and effect of BCR/ABL tyrosine kinase. 2042 53

Rho family small GTPases are important regulators of neuronal development. Defective Rho regulation causes nervous system dysfunctions including mental retardation and Alzheimer's disease. Rac1, a member of the Rho family, regulates dendritic spines and excitatory synapses, but relatively little is known about how synaptic Rac1 is negatively regulated. Breakpoint cluster region (BCR) is a Rac GTPase-activating protein known to form a fusion protein with the c-Abl tyrosine kinase in Philadelphia chromosome-positive chronic myelogenous leukemia. Despite the fact that BCR mRNAs are abundantly expressed in the brain, the neural functions of BCR protein have remained obscure. We report here that BCR and its close relative active BCR-related (ABR) localize at excitatory synapses and directly interact with PSD-95, an abundant postsynaptic scaffolding protein. Mice deficient for BCR or ABR show enhanced basal Rac1 activity but only a small increase in spine density. Importantly, mice lacking BCR or ABR exhibit a marked decrease in the maintenance, but not induction, of long-term potentiation, and show impaired spatial and object recognition memory. These results suggest that BCR and ABR have novel roles in the regulation of synaptic Rac1 signaling, synaptic plasticity, and learning and memory, and that excessive Rac1 activity negatively affects synaptic and cognitive functions.
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PMID:Regulation of synaptic Rac1 activity, long-term potentiation maintenance, and learning and memory by BCR and ABR Rac GTPase-activating proteins. 2096 34

In chronic myeloid leukemia (CML) cells from different stages of maturation may have differential expression of BCR-ABL at both messenger RNA (mRNA) and protein level. However, the significance of such differential expression to clinical disease behavior is unknown. Using the CML-derived, BCR-ABL expressing cell line, K562, distinct plastic-adherent (K562/Adh) and nonadherent (K562/NonAdh) subpopulations were established and then analyzed both as single cells and as bulk cell populations. BCR-ABL mRNA was upregulated in K562/Adh compared with K562/NonAdh cells in both single cell and bulk population analyses (p < 0.0001). Similarly, phosphorylation of BCR protein was upregulated in K562/Adh, compared with K562/NonAdh cells (63.42% vs. 23.1%; p = 0.007), and these two K562 subpopulations were found to express significantly different microRNA species. Furthermore, treatment with the BCR-ABL tyrosine kinase inhibitor, imatinib, reduced cell viability more rapidly in K562/NonAdh compared with K562/Adh cells (p < 0.005) both at single and bulk cell levels. This discovery of an adherent subpopulation of K562 cells with increased BCR-ABL mRNA, increased phosphorylated BCR protein expression, differential microRNA expression, and increased imatinib resistance suggests that a similar subpopulation of cells can also mediate clinical resistance to imatinib during treatment of patients with CML.
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PMID:Single-cell analysis of K562 cells: an imatinib-resistant subpopulation is adherent and has upregulated expression of BCR-ABL mRNA and protein. 2426 46