Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The first exon of the BCR gene encodes a new serine/threonine protein kinase. Abnormal fusion of the BCR and ABL genes, resulting from the formation of the Philadelphia chromosome (Ph), is the hallmark of Ph-positive leukemia. We have previously demonstrated that the Bcr protein is tyrosine phosphorylated within first-exon sequences by the Bcr-Abl oncoprotein. Here we report that in addition to tyrose 177 (Y-177), Y-360 and Y283 are phosphorylated in Bcr-Abl proteins in vitro. Moreover, Bcr tyrosine 360 is phosphorylated in vivo within both Bcr-Abl and Bcr. Bcr mutant Y177F had a greatly reduced ability to transphosphorylate casein and histone H1, whereas Bcr mutants Y177F and Y283F had wild-type activities. In contrast, the Y360F mutation had little effect on Bcr's autophosphorylation activity. Tyrosine-phosphorylated Bcr, phosphorylated in vitro by Bcr-Abl, was greatly inhibited in its serine/threonine kinase activity, impairing both auto- and transkinase activities of Bcr. Similarly, the isolation of Bcr from cells expressing Bcr-Abl under conditions that preserve phosphotyrosine residues also reduced Bcr's kinase activity. These results indicate that tyrosine 360 of Bcr is critical for the transphosphorylation activity of Bcr and that in Ph-positive leukemia, Bcr serine/threonine kinase activity is seriously impaired.
Mol Cell Biol 1996 Mar
PMID:Inhibition of Bcr serine kinase by tyrosine phosphorylation. 862 3

TEL is a member of the Ets family of transcription factors which are frequently rearranged in human leukemia. The mechanism of TEL-mediated transformation, however, is unknown. We report the cloning and characterization of a chromosomal translocation associated with acute myeloid leukemia which fuses TEL to the ABL tyrosine kinase. The TEL-ABL fusion confers growth factor-independent growth to the marine hematopoietic cell line Ba/F3 and transforms Rat-1 fibroblasts and primary murine bone marrow cells. TEL-ABL is constitutively tyrosine phosphorylated and localizes to the cytoskeleton. A TEL-ABL mutant containing an ABL kinase-inactivating mutation is not constitutively phosphorylated and is nontransforming but retains cytoskeletal localization. However, constitutive phosphorylation, cytoskeletal localization, and transformation are all dependent upon a highly conserved region of TEL termed the helix-loop-helix (HLH) domain. TEL-ABL formed HLH-dependent homo-oligomers in vitro, a process critical for tyrosine kinase activation. These experiments suggest that oligomerization of TEL-ABL mediated by the TEL HLH domain is required for tyrosine kinase activation, cytoskeletal localization, and transformation. These data also suggest that oligomerization of Ets proteins through the highly conserved HLH domain may represent a previously unrecognized phenomenon.
Mol Cell Biol 1996 Aug
PMID:Oligomerization of the ABL tyrosine kinase by the Ets protein TEL in human leukemia. 875 9

The c-ABL tyrosine kinase is activated following either the loss or mutation of its Src homology domain 3 (SH3), resulting in both increased autophosphorylation and phosphorylation of cellular substrates and cellular transformation. This suggests that the SH3 domain negatively regulates c-ABL kinase activity. For several reasons this regulation is thought to involve a cellular protein that binds to the SH3 domain. Hyperexpression of c-ABL results in an activation of its kinase, the kinase activity of purified c-ABL protein in the absence of cellular proteins is independent of either the presence or absence of a SH3 domain, and point mutations and deletions within the SH3 domain are sufficient to activate c-ABL transforming ability. To identify proteins that interact with the c-ABL SH3 domain, we screened a cDNA library by the yeast two-hybrid system, using the c-ABL SH3SH2 domains as bait. We identified a novel protein, AAP1 (ABL-associated protein 1), that associates with these c-ABL domains and fails to bind to the SH3 domain in the activated oncoprotein BCRABL. Kinase experiments demonstrated that in the presence of AAP1, the ability of c-ABL to phosphorylate either glutathione S-transferase-CRK or enolase was inhibited. In contrast, AAP1 had little effect on the phosphorylation of glutathione S-transferase-CRK by the activated ABL oncoproteins v-ABL and BCRABL. We conclude that AAP1 inhibits c-ABL tyrosine kinase activity but has little effect on the tyrosine kinase activities of oncogenic BCRABL or v-ABL protein and propose that AAP1 functions as a trans regulator of c-ABL kinase. Our data also indicate that loss of susceptibility to AAP1 regulation correlates with oncogenicity of the activated forms of c-ABL.
Mol Cell Biol 1996 Dec
PMID:c-ABL tyrosine kinase activity is regulated by association with a novel SH3-domain-binding protein. 894 60

Recent studies of the BCR-ABL fusion protein, the product of the oncogene responsible for chronic myelogenous leukemia, have identified a number of signal transduction pathways that are activated by this tyrosine kinase. In some cases, these pathways are critical mediators of the growth stimulatory effects of the oncogene on hemopoietic cells. This knowledge has been translated into therapeutic strategies that directly target BCR-ABL or the signaling pathways that BCR-ABL activates. Promising results in animal models have led to the design of Phase I clinical trials, which are in progress or will be under way shortly. These studies are among the first to target a specific genetic abnormality in human cancer.
Mol Med Today 1996 Dec
PMID:Signal transduction-based strategies for the treatment of chronic myelogenous leukemia. 901 91

BCR-ABL is a chimaeric oncogene generated by translocation of sequences from the c-ABL protein-tyrosine kinase gene on chromosome 9 into the BCR gene on chromosome 22. Alternative chimeric proteins, p210(BCR-ABL) and p190(BCR-ABL), are produced that are characteristic of chronic myelogenous leukemia and acute lymphoblastic leukemia, respectively. Their role in the aetiology of human leukemia remains to be defined. We have previously shown that the tumorigenic effect of BCR-ABL oncogenes is mediated by Bcl-2. In addition to Bcl-2, is a protein essential for transformation by BCR-ABL. However, it is not known how Bcl-2 and Ras fit together in cell transformation by BCR-ABL. The data presented here establish that Bcl-2 is a downstream target gene of the Ras signalling pathway in cells transformed by BCR-ABL, and that constitutive Ras activation results in constitutive expression of the gene. Conversely, a truncated form of the BCR-ABL, which lacks a critical BCR region required for activation of the Ras signalling pathway, failed to induce Bcl-2 expression. These results indicate that BCR-ABL prevents apoptosis by inducing Bcl-2 through a signalling pathway involving Ras and links constitutive Ras activation and Bcl-2 gene regulation. Hence, these results further imply that Ras is involved in both mitogenic signals and survival signals.
J Mol Biol 1997 Mar 28
PMID:Regulation of Bcl-2 gene expression by BCR-ABL is mediated by Ras. 909 20

The BCR/ABL fusion protein transforms myeloid stem cells. Both chronic myelogenous leukemias (CML) and a subset of acute lymphoblastic leukemias (ALL) are associated with the expression of BCR/ABL proteins. This knowledge has not yet been translated into any specific tool to control ABL driven neoplastic cells growth. CGP57148B is an ATP-competitive inhibitor of the ABL protein kinase; it has been shown to inhibit the kinase activity of ABL both in vitro and in vivo and to inhibit the growth of v-abl and bcr/abl transfectants, as well as the in vitro formation of bone marrow (BM)-derived colonies in the presence of growth factors in some CML patients. These studies were performed to investigate the activity of CGP57148B on the spontaneous proliferation of both fresh and cultured, leukemic and normal, BCR/ABL positive and negative cells, and to study its mechanism of action. Six cell lines derived from BCR/ABL+ leukemias (K562, BV173, KCL22, KU812, MC3, LAMA84), thirteen BCR/ABL negative lines, both neoplastic (KG1, SU-DHL-1, U937, Daudi, NB4, NB4.306) and derived from normal cells (PHA blasts, LAK, fibroblasts, LCL, renal epithelial cells, endothelial cells, CD34(+) cells), and 14 fresh leukemic samples were tested using a tritiated thymidine uptake assay. The in vivo phosphorylation of the BCR/ABL protein was evaluated by western blot, while apoptosis was detected by the annexin V/propidium binding test. The induction of differentiation was assayed by immunofluorescence using multiple antibodies. All six BCR/ABL+ lines showed a dose dependent inhibition of their spontaneous proliferative rate, which was not accompanied by differentiation. The treatment caused, within minutes, dephosphorylation of the BCR/ABL protein, followed in 16-24 hours by a decrease in cycling cells and induction of apoptosis. No significant inhibition of DNA synthesis was observed in any BCR/ABL negative normal or neoplastic line at concentrations </=3 microM, with the exception of fibroblasts and CD34 cells. Proliferation inhibition was observed also when using fresh samples obtained from two Ph+ ALL and 12 consecutive CML patients. Induction of apoptosis was observed in these samples too. The activity of CGP57148B can be monitored in ex vivo isolated or cultured cells using a simple and reproducible assay, without the need for exogenously added growth factors. This molecule possibly exerts its effects through the inhibition of the kinase activity of BCR/ABL and the subsequent initiation of apoptosis, without inducing cell differentiation. Some normal cells are also affected. These data support the use of CGP57148B in initial clinical studies; possible toxic effects on BM and fibroblast-derived cells will have to be closely monitored. The in vivo monitoring of patients will have to be focused on the induction of apoptosis in leukemic cells.
Blood Cells Mol Dis 1997 Dec
PMID:Inhibition of the ABL kinase activity blocks the proliferation of BCR/ABL+ leukemic cells and induces apoptosis. 944 52

Effects of cis-diamminedichloroplatinum (cisplatin) on rat kidney were investigated. Clinical parameters in rat urine and blood were studied. Blood urea nitrogen (BUN) and creatinine in blood and K+ in urine increased, but Na+ in urine decreased. Contents of total P450 and metabolic activities towards lauric acid and arachidonic acid in rat renal microsomes were not changed by cisplatin treatment. The levels of P450 isozymes (CYP4A1, 4A2, 4A8 and 2C23) were determined in rat renal microsomes by immunoblotting. The levels of CYP4A2 and 4A8 which are lauric acid omega-hydroxylases were not changed, but the levels of CYP2C23 and 4A1 were increased significantly by cisplatin treatment. Effects of clofibrate, a typical inducer for CYP4A1, on rat kidney were compared with those of cisplatin. Clofibrate induced palmitoyl CoA oxidase (a marker enzyme of peroxysome), CYP4A1, and CYP4A2 and reduced triglyceride level in plasma. Cisplatin had similar effects to clofibrate and induced peroxysomes as well as CYP4A1, although the effects were at a lesser extent than those of clofibrate. The induction levels of CYP4A1 correlated with increased levels of BUN. The present findings suggest that induction of P450 by cisplatin may take part in the renal injury or nephrotoxicity of cisplatin.
Res Commun Mol Pathol Pharmacol 1998 Jan
PMID:cis-Diamminedichloroplatinum induces peroxisomes as well as CYP4A1 in rat kidney. 952 52

Substrate specificity and other properties of a fatty acid monooxygenase system in kidney microsomes of the Japanese house musk shrew (Suncus murinus) were examined. The suncus kidney microsomes catalyzed the hydroxylation of various saturated and unsaturated fatty acids to the omega- and (omega-1)-hydroxy derivatives. Laurate was most effectively hydroxylated among saturated and unsaturated fatty acids. The specific activity (53.79 +/- 5.59 [mean +/- SD, n = 6] nmol/nmol cytochrome P450/min) of laurate in suncus kidney microsomes was very high compared with that in liver and kidney microsomes of other species. C18 unsaturated fatty acids were converted to epoxides by a cytochrome P450-dependent fatty acid monooxygenase system in suncus kidney microsomes, in addition to omega- and (omega-1)-hydroxylation products. The monooxygenase system metabolized arachidonic acid only to omega- and (omega-1)-hydroxylation products, not to epoxidation products.
Comp Biochem Physiol B Biochem Mol Biol 1998 Jan
PMID:Oxidation of fatty acids by kidney microsomes of musk shrew (Suncus murinus). 953 Aug 12

Chronic myeloid leukaemia (CML) develops when two genes, BCR on chromosome 22 and ABL on chromosome 9, recombine to form a hybrid BCR-ABL gene with leukaemogenic properties. The mechanism which underlies this recombination is unknown, but additional chromosome sites may be involved to form complex BCR-ABL rearrangements. The majority of breakpoints in BCR occur within a 5 kb major breakpoint cluster region, M-Bcr. Here, we show that the 3' part of M-Bcr recombined within, or immediately adjacent to, Alu elements at the additional sites in all five complex BCR-ABL rearrangements that have been examined so far. This is a new finding which suggests that Alu sequences have an affinity for the BCR-ABL recombination process in complex rearrangements, and provides additional evidence for the association of these elements with somatic rearrangements which cause human leukaemia. We further show that sequence motifs similar to IgH switch pentamers and consensus binding sites of the lymphoid-associated Translin protein are present on one or more participating strands at 3'M-Bcr recombination sites. Motifs similar to Translin-binding sites were also identified within the Alu consensus. Expressed sequences mapped close to the breakpoint sites on other chromosomes in three of the five cases examined.
Hum Mol Genet 1998 May
PMID:The BCR gene recombines preferentially with Alu elements in complex BCR-ABL translocations of chronic myeloid leukaemia. 953 79

We have constructed an allosterically controllable novel enzyme (designated maxizyme) that can be transcribed in vivo under the control of a human tRNA(Val) promoter. The maxizyme has sensor arms that can recognize target sequences, and in the presence of such a target sequence only, it can form a cavity that can capture catalytically indispensable Mg2+ ions. As a target for a demonstration of the potential utility of the maxizyme, we chose BCR-ABL mRNA, the translated products of which cause chronic myelogenous leukemia. Only the maxizyme (but not conventional ribozymes) had extremely high specificity and high-level activity, not only in vitro but also in cultured cells including BV173 cells derived from a patient with a Philadelphia chromosome. The maxizyme induced apoptosis only in leukemic cells with this chromosome.
Mol Cell 1998 Nov
PMID:A novel allosterically trans-activated ribozyme, the maxizyme, with exceptional specificity in vitro and in vivo. 984 34


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