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)

Two residues, tyrosine 235 and glutamic acid 237, of the ecotropic murine leukemia virus receptor (ATRC1) have been shown to be essential for receptor-mediated virus envelope binding and entry. We performed genetic analyses to examine the biochemical contribution of these residues in a productive virus-receptor interaction. Altered ATRC1 receptors bearing either a phenylalanine, a tryptophan, a histidine, or a methionine at position 235 mediated ecotropic virus entry comparable to that mediated by ATRC1. In contrast, altered ATRC1 receptors bearing alanine, threonine, serine, or proline at position 235 exhibited a 300- to 10,000-fold decrease in receptor capability. Furthermore, substitution of tyrosine or phenylalanine into the corresponding position (242) of the homologous human protein that lacks ecotropic virus receptor capability resulted in acquisition of ecotropic virus receptor function comparable to that of ATRC1. Substitution of a tryptophan or a histidine at that position of the human protein, however, resulted in a much-reduced receptor capability, suggesting a preference for a benzene ring in the hydrophobic side chain. A similar analysis of proteins substituted at position 237 revealed that aspartic acid, but not arginine or lysine, can functionally substitute for glutamic acid 237 in ATRC1 or at the corresponding position in the human protein. These results suggest a requirement for an acidic and a nearby hydrophobic amino acid for efficient ecotropic virus entry. Similar motifs have been identified in the virus binding sites of other retrovirus receptors, suggesting that the initial step of retrovirus entry may be governed by a common mechanism.
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PMID:Analysis of the murine ecotropic leukemia virus receptor reveals a common biochemical determinant on diverse cell surface receptors that is essential to retrovirus entry. 852 43

Human leukemia U937 cells are induced to undergo apoptosis by several chemotherapeutic agents; however, the cellular components involved in the process have not yet been identified. We found that an actin-cleavage activity (ACA) was activated in the VP-16-treated U937 cytosolic fraction and 15K- and 30K-actin fragments were produced. This ACA was inhibited by inhibitors of interleukin-1 beta-converting enzyme (ICE)/ced-3 family proteases, such as Z-Asp-CH2-DCB, YVAD-CHO, TPCK, TLCK, and iodoacetamide. Differing from ICE, the ACA could not process pro-IL-1 beta to mature IL-1 beta. Although ICE can cleave actin in vitro, ICE activity was not activated in the VP-16 treated U937 cells. These results indicate that actin is a potential substrate of ICE and ICE-like proteases, and that VP-16 preferentially activate an ICE-like protease, but not ICE itself, in U937 cells.
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PMID:Identification of actin as a substrate of ICE and an ICE-like protease and involvement of an ICE-like protease but not ICE in VP-16-induced U937 apoptosis. 855 75

c-kit is a tyrosine kinase receptor whose ligand is stem cell factor (SCF). Gene alteration of the c-kit extracellular domain was analysed by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) in 25 patients with myeloproliferative disorders (MPD). In the N-terminal part of the domain, mobility shifts indicating sequence alteration were detected in three of the patients, two primary myelofibrosis (PMF) and one chronic myelogenous leukaemia (CML). The subsequent sequencing revealed the same point mutations at codon 52 causing amino acid substitution (Asp-->Asn). To our knowledge this is the first report with a c-kit point mutation found in human fresh tumour cells.
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PMID:c-kit point mutation of extracellular domain in patients with myeloproliferative disorders. 855 71

To identify the regions that are important in human T-cell leukemia virus type 1 (HTLV-1) envelope function, we synthesized 23 kinds of peptides covering the envelope proteins and examined the inhibitory effect of each peptide on syncytium formation induced by HTLV-1-bearing cells. Of the 23 synthetic peptides, 2, corresponding to amino acids 197 to 216 on gp46 and 400 to 429 on gp21, inhibited syncytium formation induced by HTLV-1-bearing cells but did not affect syncytium formation induced by human immunodeficiency virus type 1-producing cells. The peptide concentrations giving 50% inhibition of syncytium formation for gp46 197 to 216 and gp21 400 to 429 were 14.9 and 6.0 microM, respectively. A syncytium formation assay with overlapping synthetic peptides containing amino acids 175 to 236 and 391 to 448 of the envelope proteins showed that syncytium formation was inhibited by peptides that contained the amino acid sequences 197 to 205 (Asp-His-Ile-Leu-Glu-Pro-Ser-Ile-Pro) and 397 to 406 (Gln-Glu-Gln-Cys-Arg-Phe- Pro-Asn-Ile-Thr). These observations suggest that the two regions corresponding to amino acids 197 to 216 and 400 to 429 are involved] in HTLV-1 envelope function.
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PMID:Identification and mapping of functional domains on human T-cell lymphotropic virus type 1 envelope proteins by using synthetic peptides. 862 75

This study was undertaken to examine the role of proteases in etoposide-induced apoptosis of human leukemia HL-60 cells. We found the potent activity to produce internucleosomal DNA fragmentation in a 150 000 g supernatant of cell lysate which was prepared from etoposide-treated HL-60 cells undergoing apoptosis. This nuclear-DNA fragmenting activity could be detected when the supernatant was incubated with isolated nuclei under Mg2+-dependent conditions. On the other hand, we could not detect such activity in the supernatant of cell lysate from non-treated HL-60 cells. Treatment of the supernatant with a serine protease inhibitor, N-tosyl-L-phenylala-nylchloromethyl ketone (TPCK), abolished the DNA fragmenting activity. An inhibitor of interleukin 1-beta-converting enzyme (ICE), Z-Val-Ala-Asp-fluoromethyl ketone (VAD-FMK), had no effect on this DNA fragmenting activity in vitro. However, when the cells were incubated with etoposide in the presence of VAD-FMK, the formation of TPCK-sensitive DNA fragmenting activity was blocked. Our data indicate that serine and ICE-like proteases may be involved in etoposide-induced apoptosis at the different stages, and especially a serine protease may be closely associated with the final step for induction of internucleosomal DNA fragmentation during apoptosis in HL-60 cells.
Leukemia 1996 May
PMID:Role of serine and ICE-like proteases in induction of apoptosis by etoposide in human leukemia HL-60 cells. 865 77

The roles of interferons (IFNs) in apoptosis are not fully understood. In this study we show that in the U937 monoblastic leukemia cell line, pretreatment with IFN-gamma enhanced sensitivity to apoptosis triggered by gamma-irradiation or antitumor agents (etoposide or adriamycin), as well as by anti-Fas antibody. In addition, IFN-gamma caused an increased expression of the interleukin-1 beta-converting enzyme (Ice) gene, following strong induction of the interferon regulatory factor-1 (IRF-1) gene, the product of which is a transcriptional activator of the Ice gene. An inhibitor of ICE/Ced-3 family proteases, Z-Asp-CH2-DCB, blocked apoptosis in control cells as well as in IFN-gamma-pretreated cells. These results suggest that enhanced susceptibility of IFN-gamma-pretreated cells to apoptosis is mediated through the induction of Ice by IRF-1. This pathway is not affected by interleukin-1 beta (IL-1 beta) since neutralizing antibody against IL-1 beta failed to suppress the IFN-gamma-mediated enhancement of cell death, and IL-1 beta itself did not mimic the effect of IFN-gamma.
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PMID:Interferon-gamma induces Ice gene expression and enhances cellular susceptibility to apoptosis in the U937 leukemia cell line. 895 78

Some chemotherapeutic agents, as well as TNF and Fas, induce apoptotic cell death in tumor cells, but the cellular components involved in the process have not yet been identified. Interleukin 1 beta converting enzyme (ICE) is a mammalian homolog of CED-3, a protein required for programmed cell death in nematode Caenorhabditis elegans. We found that a selective inhibitor of ICE/ced 3 family proteases, benzyloxycarbonyl Asp CH2OC(O) 2 6,-dichlorobenzene (Z-Asp-CH2-DCB). completely blocked the apoptotic cell death of human leukemia cells caused by etoposide, camptothecin, 1-beta-D-arabinofuranosyl cytosine (Ara-C) and adriamycin. Moreover, in antitumor agent-treated U937 cells, an ICE-like (CPP32-like) protease was strongly activated. These results indicate that ICE/ ced 3 family proteases are involved in antitumor agent-induced apoptosis. Activation of ICE family proteases plays a key role in apoptosis. However, the subsequent mechanisms resulting in apoptosis are largely unknown. We identified actin as a substrate of ICE family proteases. Cleavage of actin and other substrate proteins by ICE family proteases could be critical in the ongoing process of antitumor agent-induced apoptosis in tumor cells.
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PMID:[Involvement of ICE/CED 3 family proteases in antitumor agent-induced apoptosis]. 903 Feb 33

Recent genetic and biochemical studies have implicated cysteine-dependent aspartate-directed proteases (caspases) in the active phase of apoptosis. In the present study, three complementary techniques were utilized to follow caspase activation during the course of etoposide-induced apoptosis in HL-60 human leukemia cells. Immunoblotting revealed that levels of procaspase-2 did not change during etoposide-induced apoptosis, whereas levels of procaspase-3 diminished markedly 2-3 h after etoposide addition. At the same time, cytosolic peptidase activities that cleaved DEVD-aminotrifluoromethylcoumarin and VEID-aminomethylcoumarin increased 100- and 20-fold, respectively; but there was only a 1. 5-fold increase in YVAD-aminotrifluoromethylcoumarin cleavage activity. Affinity labeling with N-(Nalpha-benzyloxycarbonylglutamyl-Nepsilon-biotin yllysyl)aspartic acid [(2,6-dimethylbenzoyl)oxy]methyl ketone indicated that multiple active caspase species sequentially appeared in the cytosol during the first 6 h after the addition of etoposide. Analysis on one- and two-dimensional gels revealed that two species comigrated with caspase-6 and three comigrated with active caspase-3 species, suggesting that several splice or modification variants of these enzymes are active during apoptosis. Polypeptides that comigrate with the cytosolic caspases were also labeled in nuclei of apoptotic HL-60 cells. These results not only indicate that etoposide-induced apoptosis in HL-60 cells is accompanied by the selective activation of multiple caspases in cytosol and nuclei, but also suggest that other caspase precursors such as procaspase-2 are present but not activated during apoptosis.
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PMID:Activation of multiple interleukin-1beta converting enzyme homologues in cytosol and nuclei of HL-60 cells during etoposide-induced apoptosis. 905 43

Accelerated programmed cell death, or apoptosis, contributes to the CD4+ T-cell depletion characteristic of infection by human immunodeficiency virus (HIV). It has therefore been proposed that limiting apoptosis may represent a therapeutic modality for HIV infection. We found, however, that T leukemia cells or peripheral blood mononuclear cells (PBMCs) exposed to HIV-1 underwent enhanced viral replication in the presence of the cell death inhibitor, N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (z-AVD-fmk). Furthermore, z-VAD-fmk, which targets the pro-apoptotic interleukin-1 beta-converting enzyme (ICE)-like proteases, stimulated endogenous virus production in activated PBMCs derived from HIV-1-infected asymptomatic individuals. These findings suggest that programmed cell death may serve as a beneficial host mechanism to limit HIV spread and that strategies to inhibit it may have deleterious consequences for the infected host.
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PMID:The inhibition of pro-apoptotic ICE-like proteases enhances HIV replication. 905 63

Myeloproliferative disorders (MPD) constitute a group of hematopoietic neoplasms at the myeloid stem cell level. Myeloid stem cells and/or progenitor cells from MPD have been considered sensitive to hematopoietic growth factors, including erythropoietin, thrombopoietin and stem cell factor (SCF). SCF is a ligand for c-kit receptor with tyrosine kinase. We analysed the gene alteration of the c-kit extracellular domain in MPD patients by PCR-SSCP and subsequent nucleotide sequencing. The point mutation in the N-terminal part of the domain, codon 52 (Asp-->Asn), was found in two patients with primary myelofibrosis and one with chronic myelogenous leukemia. We review the literature regarding the role of SCF/c-kit system in the oncogenesis of leukemia and MPD, and then discuss the significance of our finding in the context of growth advantage of the mutated clones over the normal clones.
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PMID:c-kit Point mutation in patients with myeloproliferative disorders. 916 38


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