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)

A monoclonal antibody, CML-1, raised against carrot (Daucus carota L.) nuclear-matrix proteins selectively labeled the nuclear periphery of carrot protoplasts when visualized by confocal and electron microscopy. To identify the constituent proteins of higher plant cells structurally homologous to the vertebrate nuclear lamina, we cloned overlapping cDNAs partially encoding a CML-1-recognized protein and determined the entire sequence including the open reading frame. When the deduced amino acid sequence was compared with other known protein sequences contained in major databases, no protein was found to show high sequence identity across the whole region of the protein, while the partial sequence showed strong similarities with myosin, tropomyosin, and some intermediate filament proteins. The protein, designated NMCP1, had an estimated molecular mass of 133.6 kDa and showed three characteristic domains. The central domain contains long alpha-helices exhibiting heptad repeats of apolar residues, demonstrating structural similarity to that of filament-forming proteins. The terminal domains are predominantly nonhelical and contain potential sequence motifs for nuclear localization signals. NMCP1 has many recognition motifs for different types of protein kinases, including cdc2 kinase and PKC. These results suggest that NMCP1 protein forms coiled-coil filaments and is a constituent of the peripheral architecture of the higher plant cell nucleus.
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PMID:Peripheral framework of carrot cell nucleus contains a novel protein predicted to exhibit a long alpha-helical domain. 914 34

Neutrophils from patients with Chronic Myeloid Leukemia (CML) exhibit defects in several functions. They also show altered phosphorylation-dephosphorylation patterns of several proteins on stimulation with phorbol myristate acetate--a direct activator of protein kinase C (PKC). Since PKC mediates several functions of the neutrophil, in this study we investigate the PKC isoform profile and subcellular distribution in normal and CML neutrophils in an attempt to elucidate their role in CML signalling. Our results show the presence of PKC alpha, betaI, betaII and delta in both the cell types. A distinct and clear signal was obtained for PKC alpha, the isoform reported to be absent or present in very low amounts in normal neutrophils. In addition, PKC alpha was present in significantly lower levels in CML neutrophils while the PKC delta isoform was found in significantly higher amounts in the CML cytosol as compared to that in normal cells. PKC alpha, betaI, betaII and delta isoforms could not be detected in the nucleus of unstimulated normal and CML neutrophils. The altered levels of PKC alpha and delta may be one of the causes for the defects in function exhibited by the leukemic cells.
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PMID:Protein kinase C isoforms in normal and chronic myeloid leukemic neutrophils. Distinct signal for PKC alpha by immunodetection on PVDF membrane, decreased expression of PKC alpha and increased expression of PKC delta in leukemic neutrophils. 968 Jan 9

Bryostatin-1 belongs to the family of macrocyclic lactones isolated from the marine bryozoan Bugula neritina and is a potent activator of protein kinase C (PKC). Bryostatin has been demonstrated to possess both in vivo and in vitro anti-leukaemic potential. In samples derived from chronic myeloid leukaemia (CML) patients, it has been demonstrated that bryostatin-1 induces a macrophage differentiation, suppresses colony growth in vitro and promotes cytokine secretion from accessory cells. We investigated the effect of bryostatin-1 treatment on colony-forming unit-granulocyte macrophage (CFU-GM) capacity in the presence of accessory cells, using mononuclear cells, as well as in the absence of accessory cells using purified CD34-positive cells. Cells were obtained from 14 CML patients as well as from nine controls. Moreover, CD34-positive cells derived from CML samples and controls were analysed for stem cell frequency and ability using the long-term culture initiating cell (LTCIC) assay at limiting dilution. Individual colonies derived from both the CFU-GM and LTCIC assays were analysed for the presence of the bcr-abl gene with fluorescence in situ hybridization (FISH) to evaluate inhibition of malignant colony growth. The results show that at the CFU-GM level bryostatin-1 treatment resulted in only a 1.4-fold higher reduction of CML colony growth as compared to the control samples, both in the presence and in the absence of accessory cells. However, at the LTCIC level a sixfold higher reduction of CML growth was observed as compared to the control samples. Analysis of the LTCICs at limiting dilution indicates that this purging effect is caused by a decrease in output per malignant LTCIC combined with an increase in the normal stem cell frequency. It is concluded that bryostatin-1 selectively inhibits CML growth at the LTCIC level and should be explored as a purging modality in CML.
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PMID:Effects of bryostatin-1 on chronic myeloid leukaemia-derived haematopoietic progenitors. 1018 83

In chronic myelogenous leukemia (CML), the oncogene bcr-abl encodes a dysregulated tyrosine kinase that inhibits apoptosis. We showed previously that human erythroleukemia K562 cells are resistant to antineoplastic drug (taxol)-induced apoptosis through the atypical protein kinase C iota isozyme (PKC iota), a kinase downstream of Bcr-Abl. The mechanism(s) by which PKC iota mediates cell survival to taxol is unknown. Here we demonstrate that PKC iota requires the transcription factor nuclear factor-kappaB (NF-kappaB) to confer cell survival. At apoptosis-inducing concentrations, taxol weakly induces IkappaB(alpha) proteolysis and NF-kappaB translocation in K562 cells, but potently induces its transcriptional activity. Inhibition of NF-kappaB activity (by blocking IkappaB(alpha) degradation) significantly sensitizes cells to taxol-induced apoptosis. Likewise, K562 cells expressing antisense PKC iota mRNA or kinase dead PKC iota (PKC iota-KD) are sensitized to taxol; these cells are rescued from apoptosis by NF-kappaB overexpression. Expression of constitutively active PKC iota (PKC iota-CA) upregulates NF-kappaB transactivation and rescues cells from apoptosis in the absence of Bcr-Abl tyrosine kinase activity. Using a chimeric GAL4-RelA transactivator, we find that taxol potently activates GAL4-RelA-dependent transcription. This activation was further upregulated by expression of PKC iota-CA and inhibited by expression of PKC iota-KD. Our results indicate that RelA transactivation is an important downstream target of the PKC iota-mediated Bcr-Abl signaling pathway and is required for resistance to taxol-induced apoptosis.
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PMID:NF-kappaB/RelA transactivation is required for atypical protein kinase C iota-mediated cell survival. 1152 Nov 90

Erythrocytes are the most abundant cells in blood and carry out the vital function of oxygen transport. These cells lack nuclei and do not synthesise new proteins. Their cellular responses are modulated entirely by post-translational modifications in existing proteins. Phosphorylation mediated by protein kinase C (PKC) plays a significant role in red cell physiology. To date PKC alpha and zeta are the only isoforms reported to be expressed in erythrocytes. Upon activation they influence cytoskeletal integrity and erythrocyte functions. In this study we report for the first time the presence of PKC iota and PKC mu in addition to PKC alpha and zeta in human erythrocytes. All isoforms were present only in the cytosolic fraction. PKC alpha was the only isoform that translocated to the membrane upon stimulation with phorbol myristate acetate (PMA). It could thus mediate several of the reported PMA-regulated membrane modifications. Investigations on alterations in PMA-mediated phosphorylation of erythrocyte skeletal components in disorders such as chronic myeloid leukaemia can now focus on PKC alpha, which is the only isoform in erythrocytes, which translocates to the membrane on stimulation of the cells.
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PMID:Protein kinase C isoforms in human erythrocytes. 1166 2

Advanced glycation end products (AGEs) play an important role in the development of angiopathy in diabetes mellitus and atherosclerosis. Here, we show that adducts of N(epsilon)-(carboxymethyl)lysine (CML), a major AGE, and bovine serum albumin (CML-BSA) stimulated gamma-glutamylcysteine synthetase (gamma-GCS), which is a key enzyme of glutathione (GSH) synthesis, in RAW264.7 mouse macrophage-like cells. CML-BSA stimulated the expression of gamma-GCS heavy subunit (h) time- and dose-dependently and concomitantly increased GSH levels. CML-BSA also stimulated DNA-binding activity of activator protein-1 (AP-1) within 3h, but the stimulatory effect decreased in 5h, and nuclear factor-kappaB (NF-kappaB) with a peak activity at 1h and the stimulatory effect diminished in 3h. Studies of luciferase activity of the gamma-GCSh promoter showed that deletion and mutagenesis of the AP-1-site abolished CML-BSA-induced up-regulation, while that of NF-kappaB-site did not affect CML-BSA-induced activity. CML-BSA also stimulated the activity of protein kinase C, Ras/Raf-1, and MEK/ERK1/2. Inhibition of ERK1/2 abolished CML-BSA-stimulated AP-1 DNA-binding activity and gamma-GCSh mRNA expression. Our results suggest that induction of gamma-GCS by CML adducts seems to increase the defense potential of cells against oxidative stress produced during glycation processes.
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PMID:Nepsilon-(Carboxymethyl)lysine induces gamma-glutamylcysteine synthetase in RAW264.7 cells. 1214 23

Although differentiation of leukemic blasts to dendritic cells (DC) has promise in vaccine strategies, the mechanisms underlying this differentiation and the differences between leukemia and normal progenitor-derived DC are largely undescribed. In the case of chronic myeloid leukemia (CML), understanding the relationship between the induction of DC differentiation and the expression of the BCR-ABL oncogene has direct relevance to CML biology as well as the development of new therapeutic approaches. We now report that direct activation of protein kinase C (PKC) by the phorbol ester PMA in the BCR-ABL(+) CML cell line K562 and primary CML blasts induced nonterminal differentiation into cells with typical DC morphology (cytoplasmic dendrites), characteristic surface markers (MHC class I, MHC class II, CD86, CD40), chemokine and transcription factor expression, and ability to stimulate T cell proliferation (equivalent to normal monocyte-derived DC). PKC-induced differentiation was associated with down-regulation of BCR-ABL mRNA expression, protein levels, and kinase activity. This down-regulation appeared to be signaled through the mitogen-activated protein kinase pathway. Therefore, PKC-driven differentiation of CML blasts into DC-like cells suggests a potentially novel strategy to down-regulate BCR-ABL activity, yet raises the possibility that CML-derived DC vaccines will be less effective in presenting leukemia-specific Ags.
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PMID:Induced dendritic cell differentiation of chronic myeloid leukemia blasts is associated with down-regulation of BCR-ABL. 1290 78

Bcr-Abl protein tyrosine kinase (PTK) activity is a feature of chronic myeloid leukaemia and confers a survival advantage on haemopoietic progenitor cells. We have expressed conditional mutant of the Bcr-Abl PTK in the FDCP-Mix A4 multipotent haematopoietic cell line in order to examine the molecular mechanisms whereby Bcr-Abl PTK leads to enhanced cell survival under conditions in which normal cells die. Activation of Bcr-Abl PTK does not phosphorylate or activate either ERK-1/2 or JAK-2/STAT-5b, suggesting that these signal transduction pathways are not involved in Abl PTK-mediated suppression of apoptosis in FDCP-Mix cells. However, protein kinase C (PKC) does have a role to play. Inhibition of PKC results in a reversal of Bcr-Abl PTK-mediated survival in the absence of growth factor and Bcr-Abl stimulates translocation of the PKCbetaII isoform to the nucleus. Furthermore, expression of a constitutively activated PKCbetaII in haemopoietic progenitor FDCP-Mix cells stimulates enhanced cell survival when IL-3 is withdrawn. However, expression of this constitutively activated PKC isoform does not suppress cytotoxic drug-induced apoptosis. Thus Bcr-Abl PTK has pleiotropic effects which can suppress cell death induced by a number of stimuli.
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PMID:Bcr-Abl-mediated molecular mechanism for apoptotic suppression in multipotent haemopoietic cells: a role for PKCbetaII. 1463 85

The protein kinase C (PKC) family of serine/threonine kinases plays an important role in numerous cancer signaling pathways, including those downstream of the bcr-abl oncogene. We demonstrated previously that atypical PKCiota is required for Bcr-Abl-mediated resistance of human K562 chronic myelogenous leukemia (CML) cells to Taxol-induced apoptosis. Here, we report that the pattern of PKC isozyme expression characteristic of CML cells is regulated by Bcr-Abl. When Bcr-Abl was expressed in Bcr-Abl-negative HL-60 promyelocytic leukemia cells, expression of the PKCbetaI, PKCbetaII, and PKCiota genes was induced, whereas expression of the PKCdelta gene was reduced to levels similar to those found in CML cells. Given the importance of PKCiota in Bcr-Abl-mediated transformation, we characterized the mechanism by which Bcr-Abl regulates PKCiota expression. A 1200-bp PKCiota promoter construct isolated from genomic DNA was highly active in Bcr-Abl-positive K562 cells and was activated when Bcr-Abl-negative cells were transfected with Bcr-Abl. Bcr-Abl-mediated induction of the PKCiota promoter was dependent upon MEK1/2 activity, but not phosphatidylinositol 3-kinase or p38 MAPK activity. Mutational analysis of the PKCiota promoter revealed a region between 97 and 114 bp upstream of the transcriptional start site that is responsible for Bcr-Abl-mediated regulation. Mutation of a consensus Elk1-binding site within this region abolished Bcr-Abl-mediated regulation. We conclude that Bcr-Abl regulates PKCiota expression through the MEK-dependent activation of an Elk1 element within the proximal PKCiota promoter. Our results indicate that Bcr-Abl-mediated transformation involves transcriptional activation of the PKCiota gene, which in turn is required for Bcr-Abl-mediated chemoresistance.
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PMID:Bcr-Abl regulates protein kinase Ciota (PKCiota) transcription via an Elk1 site in the PKCiota promoter. 1467 Sep 60

Short 21-mer double-stranded/small-interfering RNAs (ds/siRNAs) were designed to target bcr-abl mRNA in chronic myelogenous leukemia. The ds/siRNAs were transfected into bcr-abl-positive K-562 (derived from blast crisis chronic myelogenous leukemia), using lipofectamine. Penetrating of ds/siRNAs into the cells was detected by fluorescent confocal microscopy, using fluorescein-labeled ds/siRNAs. The cells were treated with mix of three siRNA sequences (3 x 60 nM) during 6 days with three repetitive transfections. The siRNA-treatment was accompanied with significant reduction of bcr-abl mRNA, p210, protein tyrosine kinase activity and cell proliferation index. Treatment of cells with Glivec (during 8 days with four repetitive doses, 180 nM single dose) resulted in analogous reduction of cell proliferation activity, stronger suppression of protein tyrosine kinase activity, and very low reduction of p210. siRNA-mix and Glivec did not affect significantly the viability of normal lymphocytes. Microarray analysis of siRNA- and Glivec-treated K-562 cells demonstrated that both pathways of bcr-abl suppression were accompanied with overexpression and suppression of many different oncogenes, apoptotic/antiapoptotic and cell proliferation factors. The following genes of interest were found to decrease in relatively equal degree in both siRNA- and Glivec-treated cells: Bcd orf1 and orf2 proto-oncogene, chromatin-specific transcription elongation factor FACT 140-kDa subunit mRNA, gene encoding splicing factor SF1, and mRNA for Tec protein tyrosine kinase. siRNA-mix and Glivec provoked overexpression of the following common genes: c-jun proto-oncogene, protein kinase C-alpha, pvt-1 oncogene homologue (myc activator), interleukin-6, 1-8D gene from interferon-inducible gene family, tumor necrosis factor receptor superfamily (10b), and STAT-induced STAT inhibitor.
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PMID:Suppression of bcr-abl synthesis by siRNAs or tyrosine kinase activity by Glivec alters different oncogenes, apoptotic/antiapoptotic genes and cell proliferation factors (microarray study). 1525 64


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