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)

Various transplanted leukemias and normal tissues of the mouse were tested for asparagine synthetase activity. Leukemias susceptible to suppression by asparaginase have little or no synthetase activity. In contrast, leukemias insensitive to asparaginase exhibit substantial and often very high asparagine synthetase activity. Asparaginase-resistant variants of sensitive leukemias also have considerable synthetase activity. Thus the requirement by certain malignant cells of exogenous asparagine, which entails sensitivity to asparaginase, may be ascribed to lack of asparagine synthetase. Development of asparaginase-resistant variants from asparaginase-sensitive lines is consistently associated with acquisition of asparagine synthetase activity.
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PMID:Asparagine synthetase activity of mouse leukemias. 568 13

A series of 11 asparagines substituted on N4 was prepared and evaluated for their ability to inhibit the growth of L5178Y leukemia cell cultures. These cells require an exogenous source of L-asparagine and should be sensitive to an asparagine antimetabolite. The compounds were prepared by reaction of phthalylaspartic anhydride with a primary or secondary amine, followed by removal of the phthalyl group with hydrazine. One compound, N,N-dibenzylasparagine, showed significant activity. Additional study of asparagine derivatives bearing large, lipophilic groups at N4 is warranted.
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PMID:Synthesis and anticancer activity of asparagine analogs. 610 52

The nature of the carbohydrate chains in the major envelope glycoprotein of murine leukemia virus, gp70, and its cellular precursor has been investigated. A difference in the oligosaccharide composition of gp70 from an ecotropic murine leukemia virus (Akv) and three recombinant dual-tropic viruses [mink cell focus-inducing viruses (MCFs)] derived from Akv was demonstrated. Glycosidase digestion and gel filtration were utilized to identify the two classes of N-asparagine-linked oligosaccharides, high-mannose and complex. The gp70 of the ecotropic virus contained only N-linked oligosaccharides of the complex type. In contrast, the gp70s of the dual-tropic viruses contained both high-mannose and complex oligosaccharides. Analysis of gp70 glycopeptides from an MCF-related xenotropic virus showed an elution profile similar, but not identical, to profiles of the MCFs. The gp70 precursors isolated from cells infected with Akv or MCF virus contained N-linked oligosaccharides that were exclusively of the high-mannose type. Comparison of the high-mannose oligosaccharides of the MCF gp70 precursors with those of the corresponding gp70s indicated that very little further processing of the high-mannose residues in the gp70s had occurred. The presence of the high-mannose oligosaccharides in the envelope glycoprotein of the dual-tropic viruses results from altered carbohydrate processing. The conservation of this altered carbohydrate pattern in a number of hosts and under various conditions of growth suggests that the viral protein structure is the primary factor in determining the different mode of glycosylation of the MCF gp70s. Thus, these viral glycoproteins provide an important model system for studying the relationship between protein structure and patterns of glycosylation.
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PMID:Differences in glycosylation patterns of closely related murine leukemia viruses. 624 74

Addition of asparagine-linked oligosaccharides to nascent murine leukemia virus (MuLV)-encoded membrane glycoproteins was inhibited either completely by tunicamycin or specifically at Asn-X-Thr glycosylation sites by incorporation of the threonine analogue beta-hydroxynorvaline. In conditions of partial analogue substitution, a series of subglycosylated components is formed which are related by a constant apparent Mr difference when assayed by polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulfate. The total number of asparagine-linked oligosaccharides is then estimated by dividing the measured apparent Mr of one oligosaccharide into the total apparent Mr difference between the complete glycoprotein and the polypeptide chain that is synthesized in cells incubated with tunicamycin. Correct results were obtained using glycoproteins with known numbers of oligosaccharides. Our analyses indicate that the gp70 membrane envelope glycoproteins of certain ecotropic MuLVs contain seven oligosaccharides, whereas the GIX+ antigen-containing variant gp70 contains one fewer Asn-X-Thr-linked oligosaccharide. The membrane glycoprotein encoded by the gag gene of Friend MuLV contains only one asparagine-linked oligosaccharide. Similarly, the gp55 membrane glycoprotein encoded by Friend erythroleukemia virus contains four asparagine-linked oligosaccharides. Pulse-chase and cell surface iodination analyses indicate that MuLV membrane envelope glycoprotein processing by partial proteolysis and transport to the cell surface can be efficiently blocked by structural perturbations caused by incorporation of different amino acid analogues or by loss of oligosaccharides. Our data also suggest that loss of oligosaccharides may expose new antigenic sites in viral membrane glycoproteins and increase their susceptibility to intracellular proteolysis.
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PMID:Glycosylation and intracellular transport of membrane glycoproteins encoded by murine leukemia viruses. Inhibition by amino acid analogues and by tunicamycin. 629 17

The complete amino acid sequence of glycoprotein gp71A of Friend murine leukemia virus (F-MuLV) is presented. The protein moiety of gp71A was digested with Staphylococcus aureus (SV8) protease, trypsin, and thermolysin. The sequences of the peptides were determined by the micro dansyl Edman procedure. gp71A is composed of 445 amino acid residues and contains eight oligosaccharide side chains, which are attached exclusively to asparagine by N-glycosyl bonds primarily in the COOH-terminal half of the polypeptide. gp71A is rich in proline (49 residues), tryptophan (16 residues), and cysteine (19 residues). Proline has the highest molar content (11%) of all amino acids. The prolines cluster in two segments. The most interesting one stretches between residue 233 and residue 283 and contains 18 prolines within 51 amino acids. This proline-rich domain most likely forms a flexible polyproline helix. The comparison of gp70 of Moloney murine leukemia virus (Mo-MuLV gp70) with F-MuLV gp71A revealed that 70 amino acids have been exchanged and 9 residues have been deleted from Mo-MuLV gp70. The most striking alterations have taken place within the large polyproline segment (residues 247 to 281). In this part of the molecule 7 amino acids have been deleted in Mo-MuLV and 18 residues have been replaced. This evidence supports the proposal of Shinnick et al. [Shinnick, T. M., Lerner, R. A. & Sutcliffe, J. G. (1981) Nature (London) 293, 543-548] that this area is a "hot spot" for recombination.
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PMID:Complete amino acid sequence and glycosylation sites of glycoprotein gp71A of Friend murine leukemia virus. 631 May 44

We isolated and characterized two spontaneous, weakly leukemogenic mutants of Rauscher spleen focus-forming virus (R-SFFV) that contain mutations in nonoverlapping regions of the membrane envelope (env) glycoprotein gene. As reported previously (M. Ruta and D. Kabat, J. Virol. 35:844-853, 1980), the replication-defective R-SFFV encodes a membrane glycoprotein with an apparent Mr of 54,000 (gp54) which is structurally and immunologically related to the membrane envelope glycoproteins of dual-tropic murine leukemia viruses. Mutant R-SFFV clones 3-25 and 4-3 encode abnormally sized gp54-related glycoproteins with apparent Mrs of 52,000 (gp52) and 45,000 (gp45), respectively. Northern and Southern blot analyses of the mutant R-SFFV nucleic acids indicated that an insertion has occurred in the 3-25 env gene and that a deletion has occurred in the 4-3 env gene. Furthermore, restriction endonuclease analyses and comparisons of the fragmentation patterns of the wild-type and mutant glycoproteins generated by partial proteolysis with Staphylococcus aureus V8 protease indicated that the mutations affect nonoverlapping domains of the envelope glycoprotein (amino-terminal fragment affected in 3-25 glycoprotein and carboxyl-terminal fragment affected in 4-3 glycoprotein). Glycosylation inhibition studies indicated that the reduced size of gp52 is caused at least partly by loss of an asparagine-linked oligosaccharide. In addition, these mutant viruses have dramatically reduced leukemogenicities compared with wild-type R-SFFV. We conclude that the gp54 structural gene is required for initiation or amplification of the splenic erythroblast hyperplasia which characterizes the preleukemic phase of Rauscher disease.
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PMID:Reduced leukemogenicity caused by mutations in the membrane glycoprotein gene of Rauscher spleen focus-forming virus. 631 40

The trisaccharide-containing anthracyclines aclacinomycin A (ACM) and marcellomycin (MCM) have been shown by our laboratory to be potent inducers of HL-60 leukemia cell maturation, while the monosaccharide-containing anthracyclines Adriamycin and pyrromycin were inactive and significantly less potent, respectively, as initiators of the differentiation of these malignant cells. We have now observed that ACM and MCM are potent inhibitors of both total glycoprotein synthesis and the formation of lipid-linked oligosaccharide intermediates in intact HL-60 cells. This inhibitory activity was both concentration and time dependent and was maximal after 12 hr exposure to 30 nM ACM or MCM, conditions under which both cell growth and total protein synthesis were maintained at levels equal to those of untreated cells. In contrast, exposure of HL-60 cells to pyrromycin or Adriamycin, even at cytotoxic concentrations, did not result in specific decreases in the synthesis of glycoproteins containing asparagine-linked oligosaccharides. Maximum inhibition of the formation of lipid-linked intermediates by ACM or MCM preceded the loss of cell surface transferrin-binding activity (maximal at 24 hr), which in turn preceded the minimal exposure time necessary for significant induction of differentiation by either of the active anthracyclines (36 hr). These findings demonstrate a new biochemical site of action for ACM and MCM and suggest that this activity is involved in the induction of terminal differentiation of HL-60 leukemia cells by these antitumor agents.
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PMID:Inhibition of glycoprotein biosynthesis by the inducers of HL-60 cell differentiation, aclacinomycin A and marcellomycin. 632 26

The functions of asparagine-linked oligosaccharides on the PrENV protein of Friend mink cell focus-inducing (FrMCF-1) murine leukemia virus were investigated by examining the effect of two inhibitors of different stages of the biosynthetic pathway of these sugar substituents on the synthesis and processing of the viral proteins. Treatment of virus-producing cells with tunicamycin totally inhibited the glycosylation of PrEnv, and resulted in the formation of a nonglycosylated form of the protein of molecular weight 62 kDa. This component was not proteolytically processed inside the cells, and neither it nor any derivative proteins were incorporated into extracellular virions. Treatment of cells with 1-deoxynojirimycin (DNM), which inhibits the cellular glucosidases normally involved in removal of the three glucose residues present on the initially transferred oligosaccharide chains, resulted in the intracellular accumulation of a slightly larger than normal form of PrENV, and decreased levels of cell-associated gp70. Only gp70 was detected on the cell surface. The bulk of the gp70 produced in the presence of the drug was aberrantly glycosylated, and contained decreased levels of complex and increased numbers of high mannose oligosaccharides; almost all of the gp70 molecules however, contained at least one complex sugar chain. Decreased incorporation of both env and gag proteins into extracellular virions was observed, despite the fact that the gag proteins were processed normally intracellularly; in contrast, DNM treatment of Gazdar murine sarcoma virus-infected HTG2 cells, which produce only gag but not env proteins, did not inhibit the release of extracellular virus. Ultrastructural examination of FrMCF-infected cells treated with DNM indicated the presence of large numbers of intracytoplasmic vacuoles, many of which contained viral particles. These studies indicate that the normal maturation process involved in the formation of complex oligosaccharides is necessary to obtain efficient transport to the plasma membrane and proteolysis of PrEnv, and also provide evidence suggesting a role for the env proteins in regulating assembly of gag proteins into virions.
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PMID:Studies with inhibitors of oligosaccharide processing indicate a functional role for complex sugars in the transport and proteolysis of Friend mink cell focus-inducing murine leukemia virus envelope proteins. 633 Sep 91

DL-threo-beta-Fluoroasparagine (DL-threo-beta-F-Asn) inhibited the growth of murine leukemia L1210 cells and three human leukemia cell lines in culture. Fifty % inhibiting dose values ranged between 30 and 50 microM DL-threo-beta-F-Asn. L1210 cells were not sensitive to DL-erythro-beta-fluoroasparagine, DL-threo-beta-fluoroaspartic acid, or DL-erythro-beta-fluoroaspartic acid at 300 microM, the highest dose studied. The antileukemia activity of DL-threo-beta-F-Asn was studied in further detail using the L1210 model system. Inhibition of growth in culture was prevented by L-asparagine but not by D-asparagine. Inhibition of growth of L1210 cells incubated for 40 hr in the presence of 300 microM DL-threo-beta-F-Asn was reversed after DL-threo-beta-F-Asn removal. Treatment for longer periods of time resulted in cell lysis. DL-threo-beta-F-Asn at doses of 250 mg/kg increased life span in mice bearing L1210 tumors by 60%. These results demonstrate the chemotherapeutic potential of the amino acid analogue DL-threo-beta-F-Asn.
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PMID:Antitumor activity of DL-threo-beta-fluoroasparagine against human leukemia cells in culture and L1210 cells in DBA mice. 649 22

Precursor polyproteins containing translational products of the gag gene of Moloney murine leukemia virus were purified by gel electrophoresis and cleaved into large fragments by hydroxylamine, mild acid hydrolysis, or cyanogen bromide. The hydroxylamine cleavage method (specific for asparagine-glycine bonds) was adapted especially for this study. The electrophoretic mobility and antigenicity of the fragments and, in some cases, the presence or absence of [35S]methionine revealed detailed information on the structure of Pr65gag, gPr80gag, and Pr75gag (the unglycosylated variant of gPr80gag formed in vivo in the presence of tunicamycin or in vitro in a reticulocyte cell-free system). When compared with Pr65gag, gPr80gag contains 7,000 daltons of additional amino acids, presumably as, or as part of, a leader sequence at or very close to its N terminus. We present evidence that this leader may have replaced part of the p15 sequence. Furthermore, gPr80gag contains three separate carbohydrate groups. One is attached to the presumed leader sequence or to the p15 domain, and two are attached to the p30 domain. Each of the Moloney murine leukemia virus gag precursor proteins Pr65gag, gPr80gag, and Pr75gag corresponds with a read-through product into the pol gene. We designated these products Pr180gag-pol, gPr200gag-pol, and Pr190gag-pol (the unglycosylated variant of gPr200gag-pol), respectively. gPr200gag-pol contains all of the extra amino acids and carbohydrate groups present in gPr80gag and at least one carbohydrate group in its pol sequences.
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PMID:Structure of glycosylated and unglycosylated gag and gag-pol precursor proteins of Moloney murine leukemia virus. 660 20


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