Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumor-promoting phorbol esters such as phorbol 12-myristate 13-acetate (PMA) induce the monocytoid differentiation of HL-60 human leukemia cells. The cellular receptor for PMA is protein kinase C. However, cellular events distal to protein kinase C phosphorylation are also critical steps toward differentiation. These events may include specific programs of oncogene transcription that have been associated with phorbol ester-induced leukemic cell differentiation. Recently, it has been found that topoisomerase II could be activated by protein kinase C-mediated serine phosphorylation and that PMA treatment of HL-60 cells enhanced extractable topoisomerase II from these cells. Additionally, topoisomerase II-reactive antineoplastic drugs could block PMA-induced differentiation of HL-60. This enzyme has been implicated in gene regulation, and drug-induced, topoisomerase II-mediated DNA cleavage sites have been identified within cellular oncogenes. Thus, topoisomerase II could play a critical role in the signal transduction cascade leading from PMA-protein kinase interaction to monocytoid differentiation. We have examined this relationship between topoisomerase II and PMA-induced differentiation through measurements of drug-induced, topoisomerase II-mediated DNA cleavage (via alkaline elution) in PMA-treated HL-60 cells. Etoposide-induced DNA cleavage was reduced 10-fold in HL-60 cells treated with 10 nM PMA for 24 h. Neither dimethyl sulfoxide (which produces granulocytoid differentiation) nor non-differentiation-inducing phorbol esters could produce this effect. The decreased cleavage was not due to a PMA-induced inhibition of cell-associated etoposide and was demonstrable in nuclei isolated from PMA-treated cells. The decrease was not simply related to decreased cellular proliferation rate as reflected in the inhibition of DNA synthesis because conditions leading to marked inhibition of DNA synthesis did not necessarily inhibit etoposide-induced DNA cleavage. By contrast, lower concentrations of PMA inhibited etoposide-mediated DNA cleavage disproportionately compared with PMA effects on DNA synthesis. Interestingly, PMA reduced cleavage induced by the topoisomerase II-reactive DNA intercalator 4'-(9-acridinylamino)methanesulfon-m-anisidide by 2-fold, suggesting that specific drug-DNA interactions could partially overcome the PMA-induced effect that resulted in decreased etoposide-induced, topoisomerase II-mediated DNA cleavage. Nuclear proteins in 0.35 M NaCl extracts from untreated or PMA-treated HL-60 cells were virtually identical in topoisomerase II activity and in topoisomerase II-associated drug sensitivity.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Effect of phorbol ester treatment on drug-induced, topoisomerase II-mediated DNA cleavage in human leukemia cells. 284 55

Mitogen-stimulated lymphocytes and some T-lymphocyte lines released a polypeptide called differentiation-inducing factor (DIF), which restored maturation of promyelocytic HL-60 cells and inhibited growth of leukemic and normal progenitor cells. Tumor Necrosis Factor (TNF), which has been found to be not identical with DIF, displayed similar effects. On the other hand, an antigenic relationship was shown between DIF and lymphotoxin (LT) by use of neutralizing antibodies. An activity, which cochromatographed with DIF during all purification steps, competed with binding of both rLT and rTNF to HL-60 cells. Approximately 2,000 binding sites for rLT were detected per cell, with a Kd of 330 pmol/l. Our observations are indications of a functional and an antigenic connection between DIF and LT, and indicate that TNF, LT and DIF share cell surface-binding sites. These binding sites are down regulated by activation of protein kinase-C. Results from modulation of the response indicated that the signal for differentiation might be transduced through activation of phospholipase A2. In order to understand myeloid differentiation and the effects of differentiation factors, we have pursued investigations of the biosynthesis and processing of one marker of myeloid differentiation, namely myeloperoxidase (MPO). Our results disclosed that MPO was synthesized as a larger precursor of Mr 90,000 to which a heme group was added, followed by proteolytic cleavage in pregranular structures to generate mature heavy Mr 60,000 and light Mr 12,000 subunits. Processing of MPO was independent of acidification. cDNA probes are now available for MPO, so that investigation of gene expression in relation to differentiation and induction of differentiation is facilitated.
Leukemia 1988 Dec
PMID:Myeloid cell differentiation: the differentiation inducing factors of myeloid leukemia cells. 284 93

The HZ2-feline sarcoma virus (HZ2-FeSV) is a replication-defective acute transforming feline retrovirus with oncogene homology to Abelson murine leukemia virus (A-MuLV) (P. Besmer, W.D. Hardy,Jr., E. E. Zuckerman, P. J. Bergold, L. Lederman, and H. W. Snyder, Jr. (1983) Nature (London) 303, 825-828). In contrast to A-MuLV which was isolated from a hematopoietic tumor, the HZ2-FeSV derives from a multicentric fibrosarcoma. We have molecularly cloned the HZ2-FeSV provirus from mink HZ2-FeSV nonproducer cells. The molecularly cloned HZ2-FeSV provirus is biologically active upon transfection of NIH 3T3 indicator cells. The genetic structure of the HZ2-FeSV provirus was determined by EM heteroduplex and Southern blot analysis. The HZ2-FeSV has a 6.8 kb-viral genome with the structure: 5' delta gag-abl-delta pol-delta env 3'. The abl insert, which is 1.4 kb, is located 1.9 kb from the 5' end and 3.5 kb from the 3' end of the viral genome. The 5' 1.9 kb in the HZ2-FeSV are colinear with 5' FeLV sequences, and the 3' 3.5 kb are colinear with 3' FeLV sequences, with the exception of a 0.85-kb deletion in the env gene. HZ2-FeSV v-abl and A-MuLV v-abl share 1.2 kb of abl sequences which are known to specify the protein kinase domain of the abl gene product and are necessary for fibroblast transformation in vitro. The DNA from several tumor tissues of cat 3590 from which the HZ2-FeSV was obtained was found to contain several HZ2-FeSV-related proviruses including the HZ2-FeSV. The variant HZ2-FeSVs have indistinguishable 5' gag-abl sequences; however, they differ in 3' sequences which likely do not include any abl sequences. The DNAs from fibrosarcomas obtained by inoculation of kittens with tumor extract were found to contain variant HZ2-FeSV proviruses as well. Taken together these results indicate a role for the HZ2-FeSVs in sarcomagenesis.
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PMID:Structure and origins of the HZ2-feline sarcoma virus. 288 77

Types I, II, and III protein kinase C have been shown to be products of, respectively, gamma, beta, and alpha genes of this enzyme family (Huang, F. L., Yoshida, Y., Nakabayashi, H., Knopf, J. L., Young, W. S., III, and Huang, K.-P. (1987) Biochem. Biophys. Res. Commun. 149, 946-952). Incubation of the highly purified rat brain protein kinase C isozymes with trypsin (kinase/trypsin (w/w) = 100) under identical conditions results in a preferential degradation of types I and II enzymes, whereas the type III enzyme was relatively resistant to tryptic proteolysis. Degradation of the type III enzyme by trypsin could be facilitated with the addition of Ca2+, phosphatidylserine, and dioleoylglycerol; none of these components alone was effective. Limited proteolysis of the three protein kinase C isozymes generated distinctive fragments for each isozyme, indicating that each isozyme has different trypsin-sensitive sites. Tryptic digestion of the type III protein kinase C was used as a model to determine the effects of various modulators on protein kinase C degradation. While Ca2+ and phosphatidylserine together were sufficient to convert the type III protein kinase C from a trypsin-insensitive to a -sensitive form, addition of dioleoylglycerol greatly reduced the Ca2+ requirement for such a conversion. Among the various phospholipids tested, in the presence of either dioleoylglycerol or phorbol ester, phosphatidylserine, cardiolipin, and phosphatidic acid were the most effective, and phosphatidylcholine and phosphatidylethanolamine were the least effective in supporting the digestion of type III protein kinase. Other acidic phospholipids, such as lysophosphatidylserine and phosphatidylinositol, were also effective in supporting the degradation in the presence of phorbol ester but not in the presence of dioleoylglycerol. The relevance of these proteolytic reactions to physiological responses was assessed with phorbol ester on rat basophilic leukemia RBL-2H3 cells, which contained both types II and III protein kinase C. Immunoblot analysis with the isozyme-specific antibodies revealed that phorbol ester induced a faster degradation of type II than that of type III isozyme in these cells. The results demonstrate that the various protein kinase C isozymes have different susceptibilities to proteolysis in vitro, when tested with trypsin, as well as to endogenous proteases in intact cells.
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PMID:Differential down-regulation of protein kinase C isozymes. 291 98

The synthesis and testing of potential multisubstrate inhibitors of tyrosine-specific protein kinases are described. One of the substrates, ATP, was mimicked by the known kinase inhibitor 5'-[4-(fluorosulfonyl)benzoyl]adenosine, which was covalently linked via the sulfonyl moiety to tyrosine mimics. The resulting multisubstrate inhibitors were tested for their ability to inhibit the transfer of phosphate from ATP to a protein acceptor by p60v-abl, the tyrosine kinase encoded by the transforming gene (v-abl) of the Abelson murine leukemia virus (A-MuLV). Although the series of inhibitors displayed moderately potent activity (IC50 values as low as 19 microM), the absence of large effects produced by modification of the tyrosine mimic suggests that they do not behave as multisubstrate inhibitors but bind primarily through the adenosine moiety common to all the inhibitors. This interpretation is strengthened by the finding that the inhibitors lack specificity, inhibiting a serine kinase at comparable concentrations.
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PMID:Synthesis and evaluation of multisubstrate inhibitors of an oncogene-encoded tyrosine-specific protein kinase. 1. 297 May 50

Alterations in genes that function in normal growth and development have been linked to malignant cell transformation. The mononuclear phagocyte colony-stimulating factor (CSF-1 or M-CSF) is a polypeptide growth factor synthesized by mesenchymal cells, which stimulates the survival, proliferation, and differentiation of haematopoietic cells of the monocyte-macrophage series. Multiple forms of soluble CSF-1 are produced by proteolytic cleavage of membrane-bound precursors, some of which are stably expressed at the cell surface. The c-fms proto-oncogene encodes the CSF-1 receptor, which is composed of an extracellular ligand-binding domain linked by a single membrane-spanning segment to a cytoplasmic tyrosine-specific protein kinase domain. Whereas the tyrosine kinase activity of the normal receptor is stimulated by CSF-1, mutations in the c-fms gene can constitutively activate the kinase to provide growth-stimulatory signals in the absence of the ligand. Oncogenic activation of the c-fms gene product appears to involve removal of a negative regulatory tyrosine residue near the carboxyl terminus of the receptor and one or more additional mutations that may simulate a conformational change induced by CSF-1 binding. Expression of the human c-fms gene in mouse NIH-3T3 cells confers a CSF-1 stimulated growth phenotype, indicating that receptor transduction is sufficient for fibroblasts to respond to a haematopoietic growth factor. In contrast, the v-fms oncogene induces factor-independent growth and tumorigenicity in factor-dependent myeloid cell lines, and contributes to the development of proliferative disorders of multiple haematopoietic lineages when introduced into murine bone marrow progenitors. Aberrant expression of an endogenous c-fms gene secondary to proviral insertion and transcriptional activation has also been implicated in virus-induced myeloblastic leukaemia in mice. The c-fms and CSF-1 genes have been mapped on the long arm of human chromosome 5, a region that frequently undergoes interstitial deletions in certain haematopoietic disorders including acute myelogenous leukaemia. The study of CSF-1 and its receptor should provide information concerning the role of tyrosine kinases in regulating the normal growth and differentiation of haematopoietic cells and in contributing to their malignant transformation.
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PMID:The colony-stimulating factor 1 (CSF-1) receptor (c-fms proto-oncogene product) and its ligand. 297 16

Sequences termed v-abl, which encode the protein-tyrosine kinase activity of Abelson murine leukemia virus, have been expressed in Escherichia coli as a fusion product (ptabl50 kinase). This fusion protein contains 80 amino acids of SV40 small t and the 403 amino acid protein kinase domain of v-abl. We report here the purification and characterization of this kinase. The purified material contains two proteins (Mr = 59,800 and 57,200), both of which possess sequences derived from v-abl. Overall purification was 3,750-fold, with a 31% yield, such that 117 micrograms of kinase could be obtained from 40 g of E. coli within 6-7 days. The specific kinase activity is over 170 mumol of phosphate min-1 mumol-1, comparable to the most active protein-serine kinases. Kinase activity is insensitive to K+, Na+, Ca2+, Ca2+-calmodulin, cAMP, or cAMP-dependent protein kinase inhibitor. The Km for ATP is dependent on the concentration of the second substrate. GTP can also be used as a phosphate donor. The enzyme can phosphorylate peptides consisting of as few as two amino acids and, at a very low rate, free tyrosine. Incubation of the kinase with [gamma-32P]ATP results in incorporation of 1.0 mol of phosphate/mol of protein. This reaction, however, cannot be blocked by prior incubation with unlabeled ATP. Incubation of 32P-labeled kinase with either ADP or ATP results in the synthesis of [32P]ATP. This suggests the phosphotyrosine residue on the Abelson kinase contains a high energy phosphate bond.
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PMID:Purification and characterization of a protein-tyrosine kinase encoded by the Abelson murine leukemia virus. 298 75

The feline c-fes proto-oncogene, different parts of which were captured in feline leukemia virus (FeLV) to generate the transforming genes (v-fes) of the Gardner-Arnstein (GA) strain of feline sarcoma virus (FeSV) and the Snyder-Theilen strain (ST) of FeSV, was cloned and its genetic organization determined. Southern blot analysis revealed that the c-fes genetic sequences were distributed discontinuously and colinearly with the v-fes transforming gene over a DNA region of around 12.0 kb. Using cloned c-fes sequences, complementation of GA-FeSV transforming activity was studied. Upon replacement of the 3' half of v-fesGA with homologous feline c-fes sequences and transfection of the chimeric gene, morphological transformation was observed. Immunoprecipitation analysis of these transformed cells revealed expression of high Mr fusion proteins. Phosphorylation of these proteins was observed in an in vitro protein kinase assay, and tyrosine residues appeared to be involved as acceptor amino acid.
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PMID:Molecular cloning of the feline c-fes proto-oncogene and construction of a chimeric transforming gene. 299 4

A new acute transforming feline retrovirus, the Hardy-Zuckerman 4 feline sarcoma virus (HZ4-FeSV), has been isolated from a feline fibrosarcoma. The viral genome of HZ4-FeSV contains a new oncogene designated v-kit, has the structure 5' delta gag-kit-delta pol-delta env 3' and specifies a gag-kit polyprotein of relative molecular mass 80,000. The predicted kit amino-acid sequence displays partial homology with tyrosine-specific protein kinase oncogenes. HZ4-FeSV appears to have been generated by transduction of feline c-kit sequences with feline leukaemia virus.
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PMID:A new acute transforming feline retrovirus and relationship of its oncogene v-kit with the protein kinase gene family. 300 97

During retinoic acid induced differentiation of the human promyelocyte leukemia cell line HL60 and the human myeloblast cell line RDFD along the myeloid pathway, there is marked modulation of both the cyclic adenosine 3':5'-monophosphate dependent protein kinase and the phospholipid-sensitive calcium dependent protein kinase. In order to further assess whether these kinases are intimately associated with the differentiation process, we have correlated the modulation of these enzymes and phosphorylations of their substrates with the extent of differentiation induced by various retinoid derivatives. We observed that there was a direct relationship between the degree of differentiation of the two leukemic cell lines and the elevation of the cyclic adenosine 3':5'-monophosphate dependent protein kinase and phospholipid sensitive calcium dependent protein kinase activities. In addition, the increased phosphorylation of the various substrates of these enzymes also correlates with the degree of differentiation. These observations support the hypothesis that modulation of these protein kinases and phosphorylation of their substrates are necessary steps in the differentiation process.
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PMID:Correlation between the induction of leukemic cell differentiation by various retinoids and modulation of protein kinases. 300 89


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