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)

We have purified a 30-kDa serine protease (designated RNK-Met-1) from the granules of the rat large granular lymphocyte leukemia cell line (RNK-16) that hydrolytically cleaves model peptide substrates after methionine, leucine, and norleucine (Met-ase activity). Utilizing molecular sieve chromatography, heparin-agarose, chromatography, and reverse-phase high pressure liquid chromatography, RNK-Met-1 was purified to homogeneity and 25 NH2-terminal amino acids were sequenced. By using the polymerase chain reaction, oligonucleotide primers derived from amino acids at position 14-25 and from a downstream active site conserved in other serine protease genes were used to generate a 534-base pair cDNA clone encoding a novel serine protease from RNK-16 mRNA. This cDNA clone was used to isolate a full-length 867-base pair RNK-Met-1 cDNA from an RNK-16 lambda-gt11 library. The open reading frame predicts a mature protein of 238 amino acids with two potential sites for N-linked glycosylation. The cDNA also encodes a leader peptide of at least 20 amino acids. The characteristic Ile-Ile-Gly-Gly amino acids of the NH2 terminus and the His, Asp, and Ser residues that form the catalytic triad of serine proteases were both conserved. The amino acid sequence has less than 45% identity with any other member of the serine protease family, indicating that RNK-Met-1 is distinct and may itself represent a new subfamily of serine proteases. Northern blot analysis of total cellular RNA detected a single 0.9-kilobase mRNA in the in vitro and in vivo variants of RNK-16 and in spleen-derived plastic-adherent rat lymphokine-activated killer cells. RNK-Met-1 mRNA was not detectable in freshly isolated rat splenocytes, thymocytes, brain, colon, and liver or activated nonadherent rat splenocytes and thymocytes. These data indicate that RNK-Met-1 is a serine protease with unique activity that is expressed in the granules of large granular lymphocytes.
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PMID:Purification and cloning of a novel serine protease, RNK-Met-1, from the granules of a rat natural killer cell leukemia. 144 89

Medullasin, a serine protease found in human bone marrow cells, has been shown to induce activated killer (AK) cells that lyse both natural killer (NK)-sensitive and -resistant cloned target cells from human lymphocytes. In addition to all the tested malignant cell lines, malignant cells obtained from all patients with acute myelocytic leukaemia, chronic lymphocytic leukaemia and lymphoblastic leukaemia were lysed by AK cells induced by medullasin. Maximum induction was achieved when lymphocytes were incubated at 37 degrees for 60 min in the presence of medullasin (20 micrograms/ml). The cytotoxicity of AK cells induced by medullasin treatment (200 micrograms/ml, 37 degrees for 60 min) was greater than that of lymphokine-activated killer (LAK) cells produced by 500 U/ml of interleukin-2 (IL-2). Cytokines such as IL-2 or interferon (IFN) are not considered to be involved in the medullasin induction of AK cells for the following reasons: (1) neither IL-2 nor IFN activity were detected in the supernatant of lymphocytes treated with medullasin; (2) the supernatant of lymphocytes treated with medullasin failed to induce AK cells; and (3) the presence of antibodies against IL-2 or IFN did not influence the effect of the protease. By employing monoclonal antibodies to the surface antigens of lymphocytes and a panning method using plastic dishes coated with anti-mouse IgG goat Fab', progenitor as well as effector cells were found to be CD16-positive cells.
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PMID:Induction of activated killer cells from human lymphocytes by medullasin (a serine protease in bone marrow cells). 157 95

Myeloblastin is a serine protease that has been identified in the human leukemia cell line HL-60. Down-regulation of this protease can inhibit proliferation and induce differentiation of promyelocyte-like human leukemic cells. Proteinase 3, a serine protease of human neutrophils, has been identified as the Wegener autoantigen. A high level of homology between myeloblastin and proteinase 3 has suggested that they may be a single serine protease. We have recently completed the 5'-terminal nucleotide sequence of proteinase 3 and shown that its mRNA was also expressed in HL-60 cells and in cells from patients with acute myeloid leukemia. Here we demonstrate that myeloblastin and proteinase 3 are encoded by a single mRNA.
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PMID:Wegener autoantigen and myeloblastin are encoded by a single mRNA. 168 49

We have purified a protein from the granules of the rat NK leukemia cell line (RNK) that is cytostatic to a variety of tumor cells. This protein shows no species specificity because certain tumor cell lines of mouse, rat, and human origin were equally sensitive to its growth inhibitory effects. Treatment of sensitive cells resulted in a rounding of the cells followed by homotypic aggregation into large aggregates. The granule protein was distinct from cytolysin, Na-Cbz-Lys-thiobenzylester-esterase, or leukolexin. It had a molecular mass of 29 to 31 kDa, bound strongly to heparin, was inactivated by heating at 70 degrees C for 5 min or reduction, but was stable to trypsin treatment. By using molecular sieve chromatography, heparin agarose chromatography, and reverse phase HPLC, this protein was purified to homogeneity. The first 33 amino acids of the N-terminal amino acid sequence showed complete identity to the sequence predicted from a rat serine protease gene recently cloned and designated RNKP-1. Therefore we have purified a novel serine protease and demonstrated that it has effects on the growth and morphology of certain tumor cells. Other serine proteases that were structurally related and have substantial homology with RNKP-1 at the amino acid level showed neither growth inhibitory properties nor affected the morphology of the tumor target cells we used.
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PMID:Purification of a factor from the granules of a rat natural killer cell line (RNK) that reduces tumor cell growth and changes tumor morphology. Molecular identity with a granule serine protease (RNKP-1). 172 74

A human cDNA clone encoding a novel serine protease, cytotoxic serine protease-C(CSP-C), has been isolated from a cDNA library prepared from recombinant interleukin-2 (IL-2)-activated lymphocytes of a patient with a large granular lymphoproliferative disorder. The clone has a 741-base pair open reading frame encoding a putative 246-amino acid protein. The protein sequence contains the catalytic charge relay system characteristic of a serine protease and the conserved N-terminal amino acid sequence of the mature cytotoxic lymphocyte serine proteases found in both mouse and human. The amino acid sequence of CSP-C has 71% identity with the previously reported cytotoxic serine protease-B(CSP-B)/human lymphocyte protease (HLP)/SECT and 57% identity with the granulocyte-specific serine protease cathepsin G. The homology with another lymphocyte-specific serine protease, human Hanukah factor (HF)/Granzyme A was 41%. The transcript is expressed in lymphocytes stimulated with IL-2 or IL-2 plus phytohemagglutinin (PHA). CSP-C is not expressed in B-lymphoblastoid cell lines or in the T-leukemia cell line MOLT4. The cDNA sequence suggests that the protein is expressed as a prepropeptide, as has been found in the other murine and human serine proteases of lymphocyte origin. It has recently been reported that human chromosome 14q11, in addition to containing the genes encoding cytotoxic serine protease B (CSP-B), cathepsin G, and the T-cell receptor alpha and delta genes, also includes an additional genomic DNA clone which cross-hybridized with CSP-B and cathepsin G, cathepsin-like gene-2 (CGL-2). It is likely that the CSP-C cDNA clone reported in this study corresponds to CGL-2.
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PMID:Characterization of a novel, human cytotoxic lymphocyte-specific serine protease cDNA clone (CSP-C). 240 57

Activity of a chymotrypsin-type serine protease was found in a subline of rat basophilic leukemia (RBL-2H3) cells. The protease was immunologically cross-reactive with anti-atypical mast cell protease immunoglobulin (Ig) G, and its activity was inhibited in a dose-dependent manner by the antibody. The apparent m.w. of the protease that reacted with the antibody was 25,000, which was identical with that of atypical mast cell protease in rat mucosal mast cells. These results show that the chymotrypsin type serine protease in RBL-2H3 cells is immunologically identical with atypical mast cell protease, which was first purified from rat small intestine. Immunohistochemical studies showed that the protease was located not only in intracytoplasmic granules but also in organelles synthesizing protein, such as cisternae of the rough endoplasmic reticulum, perinuclear spaces, and the Golgi apparatus. However, no immunoreactivity was demonstrated in rat basophils. The activity of the protease increased in the exponential phase of growth of RBL-2H3 cells in which some activity was also detected in the medium, and it decreased in the late stationary phase.
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PMID:A chymotrypsin-type serine protease in rat basophilic leukemia cells: evidence for its immunologic identity with atypical mast cell protease. 241 25

A new serine protease was encoded by a clone isolated from a murine cytotoxic T-lymphocyte complementary DNA library by an RNA-hybridization competition protocol. Complementary transcripts were detected in cytotoxic T lymphocytes, spleen cells from nude mice, a rat natural killer cell leukemia, and in two of eight T-helper clones (both cytotoxic), but not in normal mouse kidney, liver, spleen, or thymus, nor in several tested T- and B-cell tumors. T-cell activation with concanavalin A plus interleukin-2 induced spleen cells to express this gene with kinetics correlating with the acquisition of cytolytic capacity. The nucleotide sequence of this gene encoded an amino acid sequence of approximately 25,700 daltons, with 25 to 35 percent identity to members of the serine protease family. The active site "charge-relay" residues (His57, Asp102, and Ser195 of the chymotrypsin numbering system) are conserved, as well as the trypsin-specific Asp (position 189 in trypsin). A Southern blot analysis indicated that this gene is conserved in humans, mouse, and chicken. This serine protease may have a role in lymphocyte lysis and a "lytic cascade."
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PMID:Cloning of a cDNA for a T cell-specific serine protease from a cytotoxic T lymphocyte. 242 55

Granules that are potently cytolytic in vitro can be obtained from cytotoxic lymphocytes that kill virally infected cells and tumor cells. These granules contain pore-forming proteins and several serine proteases. Here we indicate that at least two different proteases participate in the lysis mediated by granule proteins from RNK-16 rat leukemia cells. We report twelve different mechanism-based or "suicide" isocoumarin serine protease inhibitors which have different 3- and 7-substituents that confer selectivity and reactivity towards either the chymotrypsin- ("chymase") or trypsin-like ("tryptase") protease activities of RNK-16 cells. Second order inhibition rates of inactivation (kobsd/[I]) for the RNK-16 granule proteases ranged between 164 and 22,640 M-1s-1. These new, specific and highly reactive isocoumarin serine protease inhibitors also abrogated the cytolysis mediated by lymphocytes granule proteins. The eight inhibitors with large hydrophobic or basic substituents that conferred chymase or tryptase specificities were more effective at inactivating lytic function than the four elastase-directed inhibitors with smaller substituents. All twelve new isocoumarin inhibitors blocked cytolysis at lower concentrations than 3,4-dichloroisocoumarin, a potent general mechanism-based serine protease inhibitor that also blocks RNK-16 granule protease activities and lysis.
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PMID:Selective isocoumarin serine protease inhibitors block RNK-16 lymphocyte granule-mediated cytolysis. 281 73

Characterization of glucocorticoid receptors in leukemia cells is important to understand mechanisms of glucocorticoid resistance but has been impeded by receptor fragmentation in cytosol extracts. We recently found that formation of 52- and 30-kilodalton (kD) glucocorticoid receptor fragments in cytosol of leukemia cells is due to proteolysis and is blocked by diisopropylfluorophosphate (DFP). In the present study, we identify a 28-kD serine protease in cytosol of leukemia cells that binds [3H]DFP and correlates with the formation of 52- and 30-kD receptor fragments. This protease is immunoprecipitated by antiserum to neutrophil elastase. Limited digestion of [3H]dexamethasone-21-mesylate-labeled receptors by purified neutrophil elastase produces 52- and 30-kD receptor fragments. Receptor fragmentation in the cytosol of leukemia cells in inhibited by methoxysuccinyl-alanyl-alanyl-prolyl-valyl-chloromethylketone, a highly specific inhibitor of neutrophil elastase. The addition of as few as 5% neutrophils to a lymphoid cell suspension provides sufficient elastase to produce receptor fragmentation. Our findings indicate that neutrophil elastase is responsible for receptor fragmentation in the cytosol of leukemia cells. The neutrophil elastase may be endogenous to the leukemia cells or may come from neutrophils that contaminate leukemia cell suspensions.
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PMID:Neutrophil elastase produces 52-kD and 30-kD glucocorticoid receptor fragments in the cytosol of human leukemia cells. 330 64

We have shown that cytosol samples from human leukemia cells frequently contain glucocorticoid receptor fragments that have a mol wt (Mr) of approximately 52,000. In the present study we demonstrate that the Mr approximately 52,000-receptor fragments are derived from intact glucocorticoid receptors (Mr approximately 97,000) by the action of a serine protease. Mr approximately 52,000-receptor fragments were present in cytosol from 24 of 52 leukemia cell samples. Only normal size glucocorticoid receptors were present in cytosol samples if diisopropylfluorophosphate (DFP), a potent inhibitor of serine proteases, was added to the hypotonic buffer used for cytosol preparation. Receptor proteolysis was not inhibited by hydrolyzed DFP, benzamidine, phenylmethylsulfonylfluoride, aprotinin, iodoacetamide, or mercuric chloride. The leukemia cell protease digests the receptor at a different site than chymotrypsin, which digests the intact receptor to produce a Mr approximately 40,000 receptor fragment. Receptor messenger RNA (mRNA) in S49 mouse lymphoma cells and in human leukemia cells was analyzed by Northern hybridization with a cDNA for the normal glucocorticoid receptor. Mutant S49 mouse lymphoma cells that have abnormally small glucocorticoid receptors (Mr approximately 48,000) make a 5.0-kilobase receptor transcript in addition to the normal size 6.5-kilobase receptor transcript. A normal size receptor transcript of 6.5 kilobases was present in all of the human leukemia cells whether or not Mr approximately 52,000-receptor fragments were present. Therefore, abnormalities of glucocorticoid receptor mRNA, which may give rise to the synthesis of foreshortened receptors in certain mutant mouse lymphoma cells, are apparently absent from human leukemia cells.
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PMID:Characterization of glucocorticoid receptors and glucocorticoid receptor mRNA in human leukemia cells: stabilization of the receptor by diisopropylfluorophosphate. 354 20


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