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)

The mechanisms by which interferon inhibits viral growth are only partially understood. Several enzymatic activities increase in cells shortly after treatment with interferon. One of these enzymes, oligo-isoadenylate synthetase, synthesizes (2'-5') isoadenylate oligomers which strongly stimulate the activity of a cellular ribonuclease, RNase F (ref. 7). Interferon also significantly increases the activity of a protein kinase which phosphorylates the initiation factor eIF-2 and can inhibit in vitro protein synthesis. Such interferon-induced enzymes, which affect RNA and protein metabolism, might be responsible for many of its effects on viruses. Indeed, inhibition of viral protein and RNA synthesis appears to have a major role in the antiviral state. We have now investigated possible interactions of the two enzymes with viral constituents during the course of infection and found that in two different membrane-coated RNA viruses, vesicular stomatitis virus (VSV) and Moloney murine leukaemia virus (M-MuLV), there is an accumulation of the 2'-5') oligo-isoadenylate synthetase (E) in the virions. Most of the enzyme is bound to the virion ribonucleoprotein core. The incorporation of E into the virions suggests a direct involvement of the enzyme in regulation of virus functions.
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PMID:An interferon-induced cellular enzyme is incorporated into virions. 615 96

A mouse cell line, NIH 3T3, does not respond to some of the activities of interferon. Even after treatment with high concentrations of interferon the replication of lytic viruses, such as encephalomyocarditis virus (EMCV) and vesicular stomatitis virus (VSV) is not inhibited in these cells. In contrast, interferon treatment of these same cells results in the inhibition of Moloney murine leukemia virus (MMuLV) production. We have analyzed enzymatic pathways which are induced by interferon in these cells. After interferon treatment, the level of the (2'-5')oligoadenylate [(2'-5)An] synthetase activity and the phosphorylation of the 67000-dalton protein (P1) are enhanced in NIH 3T3 cells to approximately the same level as interferon-sensitive mouse L-cells. Moreover, NIH 3T3 and L-cells, contain approximately the same levels of enzymes which inactivate (2'-5')An. Both exogenously added (2'-5')A3 or double-stranded RNA (dsRNA) failed to inhibit protein synthesis in NIH 3T3 extracts even though they were potent inhibitors of L-cell extract-directed protein synthesis. Direct measurements of the (2'-5')An-dependent ribonuclease F (RNase F) failed to detect such activity in NIH 3T3 cells. Our results, therefore, suggest that the presence of RNase F activity is necessary for the interferon-induced antiviral activity against EMCV and against VSV. The induction of protein kinase activity by interferon treatment of NIH 3T3 cells appears to have no direct effect on EMCV and VSV replication.
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PMID:A mouse cell line, which is unprotected by interferon against lytic virus infection, lacks ribonuclease F activity. 616 26

Rat embryo fibroblasts transformed by Abelson murine leukemia virus (MuLV) produce and release a transforming growth factor (TGF). Production of this factor is correlated with a tyrosine-specific protein kinase that is functionally active and is associated with the major Abelson MuLV gene product, P120. Transformation-defective mutants of Abelson MuLV do not transform cells, do not have their virus coded transforming gene product phosphorylated in tyrosine, and do not induce TGF production. Abelson MuLV-induced TGF morphologically transforms cells in culture, competes with 125I-labeled epidermal growth factor (EGF) for binding to cell receptors, and induces phosphorylation of tyrosine acceptor sites in the 160,000-dalton EGF membrane receptor. After purification to homogeneity, Abelson virus-induced TGF migrates as a single polypeptide with an apparent size of 7400 daltons as determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis.
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PMID:Transformation induced by Abelson murine leukemia virus involves production of a polypeptide growth factor. 617 40

Hybridomas secreting monoclonal antibodies directed against polyprotein gene products of the Gardner, Snyder-Theilen, and McDonough strain of feline sarcoma virus have been isolated. Antibody produced by one hybridoma recognizes immunological determinants localized within a feline leukemia virus gag gene structural component (p15) common to polyproteins encoded by each feline sarcoma virus isolate while antibody produced by a second is specific for p30 determinants unique to P170gag-fms. Additional hybridomas secrete antibody directed against v-fes specific determinants common to the Gardner and Snyder-Theilen feline sarcoma virus-encoded polyproteins and to v-fms determinants unique to P170gas-fms polyprotein. GA P110gas-fes and ST P85gas-fes immunoprecipitated by antibody directed against p15 exhibit readily detectable levels of protein kinase activity but lack such activity when precipitated by antibody specific for their acquired sequence (v-fes) components. P170gas-fms immunoprecipitated by monoclonal antibody to either p15 or p30 lacks detectable levels of autophosphorylation but represents a substrate for the GA P110gag-fes and ST P85gag-fes enzymatic activities. These findings argue that the v-fes-associated protein kinase represents an intrinsic property of the v-fes gene product and recognizes tyrosine acceptor sites within polyprotein gene products of all three strains of feline sarcoma virus.
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PMID:Monoclonal antibodies specific to transforming polyproteins encoded by independent isolates of feline sarcoma virus. 618 42

Infectious leukemia virus production by two chronically infected NIH/MOL lines was strongly inhibited by interferon treatment of the cells. The corresponding degree of inhibition in JLSV-11 cells was much lower. Multiplication of encephalomyocarditis virus in all three cell lines was barely affected by interferon treatment. Replication of vesicular stomatitis virus, on the other hand, was highly sensitive to interferon in the JLSV-11 line and in one NIH/MOL line but was practically insensitive in the other NIH/MOL line. Anticellular actions of interferon were more pronounced in the JLSV-11 line than in the others. In response to interferon treatment, 2',5'-oligoadenylate synthetase activity was induced to a high level in JLSV-11 cells and to lower levels in the NIH/MOL lines. We failed to detect any 2',5'-oligoadenylate-dependent endonuclease activity in extracts of these cells. Double-stranded RNA-dependent protein kinase activity was present in extracts of interferon-treated NIH/MOL cells, but it was barely detectable in extracts of interferon-treated JLSV-11 cells. The above studies demonstrated that interferon could differentially affect the replication of three different viruses in three different cell lines, including two seemingly identical NIH/MOL lines, and that certain tentative conclusions can be drawn regarding the roles of different interferon-inducible enzyme markers in the different antiviral actions of interferons.
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PMID:Differential antiviral effects of interferon in three murine cell lines. 618 40

The human homologues of several independent viral oncogenes, each of which encodes tyrosine-specific protein kinases, have been identified. Of these, three (v-src, v-yes and v-fes/fps) are known to exhibit considerable sequence homology, particularly in the regions of their phosphorylation acceptor sites. In the present study, sequences encoding the tyrosine phosphorylation acceptor sites of the Abelson murine leukaemia virus oncogene, v-abl, and its human cellular homologue, c-abl, have been identified and their nucleic acid sequences determined. Our results establish extensive homology between this region of c-abl and acceptor domains of the v-src, v-yes and v-fes/fps family of viral oncogenes, as well as more distant relatedness to the catalytic chain of the mammalian cyclic AMP-dependent protein kinase. These findings suggest that, of the homologues of retroviral oncogenes with tyrosine protein kinase activity examined to date, all were probably derived from a common progenitor and may represent members of a diverse family of cellular protein kinases.
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PMID:Homology between phosphotyrosine acceptor site of human c-abl and viral oncogene products. 619 Dec 23

The v-abl protein is known to be a tyrosine-specific protein kinase. However, its normal cellular homolog, c-abl P150, is not detectably phosphorylated on tyrosine in vivo or in vitro. The lack of associated tyrosine kinase activity for the c-abl protein seems paradoxical since it is the c-abl-derived sequences of the v-abl protein that encode the kinase activity. We have detected an altered human c-abl protein (P210) with associated tyrosine kinase activity in the K562 leukemia cell line. K562 cells are known to have a 9:22 chromosomal translocation involving the c-abl locus and have amplified the c-able gene 4 to 8 fold. The altered P210 human c-abl is serologically and structurally related to the normal c-abl protein. A structural alteration of the human c-abl protein. K562 cells may have unmasked its associated tyrosine kinase activity. This altered c-abl protein may have important implications for a mechanism of activation of this oncogene.
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PMID:An alteration of the human c-abl protein in K562 leukemia cells unmasks associated tyrosine kinase activity. 620 66

Several independent isoltes of feline sarcoma virus (FeSV) have been described. Such viruses are apparently derived by genetic recombination between feline leukaemia virus (FeLV) genomic RNA and host cellular genetic sequences with transforming potential. Two FeSV isolates, one originally described by Gardner and the second by Snyder-Theilen, have been shown to encode polyproteins of around 115,000 molecular weight. Both polyproteins contain FeLV structural components (p15, p12) at their amino terminus in addition to nonstructural carboxyl terminal components encoded by acquired sequences within the FeSV genome. We have previously shown that Gardner FeSV P115 contains multiple sites of phosphorylation within its nonstructural component and possesses an associated protein kinase activity. In the present study we describe the expression in cells derived from a number of mammalian species, of a highly conserved celklular phosphoprotein with binding affinity for Gardner FeSV P115. This protein, designated P150, exhibits an associated protein kinase activity and is immunologically and structurally distinct from polyproteins encoded by the Gardner or Snyder-Theilen strains of FeSV.
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PMID:Feline sarcoma virus polyprotein P115 binds a host phosphoprotein in transformed cells. 625 64

Malignant transformation by mammalian RNA sarcoma viruses has previously been shown to involve a reduction in receptor sites for a well characterized 6,000-molecular weight (MW) growth-promoting substance, designated epidermal growth factor (EGF). Although Abelson murine leukaemia virus (AbLV) resembles sarcoma viruses in its ability to transform embryo fibroblasts in cell culture, AbLV induces a rapid B-cell lymphoid leukaemia rather than fibrosarcomas in vivo. The major translational product of AbLV is a highly phosphorylated polyprotein of MW 120,000 which exhibits an associated tyrosine-specific protein kinase activity and probable transforming function. We show here that AbLV transformation resembles transformation by RNA sarcoma viruses with respect to the abolition of EGF-binding sites. EGF binding is restored to control levels following loss of polyprotein expression in morphological revertants of AbLV-transformed clones and remains uninfluenced in cell lines infected with transformation-defective (td) AbLV mutants encoding polyproteins deficient in protein kinase activity. These findings indicate that AbLV transformation involves a polyprotein-associated, tyrosine-specific protein kinase activity which mediates its effect through a mechanism resulting directly or indirectly in the abolition of EGF-binding sites.
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PMID:Abelson murine leukaemia virus transformation involves loss of epidermal growth factor-binding sites. 625 69

Several transformation-defective (td) mutants of Abelson murine leukemia virus (AbLV) are described. Cells nonproductively infected with such mutants exhibited a high degree of growth contact inhibition, failed to form colonies in soft agar, lacked rescuable transforming virus, and were as susceptible as uninfected control cells to transformation by wild-type (wt) AbLV pseudotype virus. In addition, each of several td AbLV nonproductively infected cell clones analyzed was found to be nontumorigenic in vivo. Biochemical analysis of td mutant AbLV-infected clones revealed levels of expression of the major AbLV translational product, P120, and a highly related 80,000-Mr AbLV-encoded protein, P80, at concentrations analogous to those in wt AbLV-transformed cells. Although the AbLV-specific 120,000-Mr polyproteins expressed in td mutant AbLV-infected clones were indistinguishable from those in wt AbLV-transformed lines with respect to molecular weight and [35S]methionine tryptic peptide composition, they each differed from wt AbLV P120 in their patterns of post-translational phosphorylation. A previously described AbLV-associated protein kinase activity is shown to recognize as substrate a major tyrosine-specific acceptor site(s) contained within a single well-resolved tryptic peptide common to both AbLV P120 and P80. In vitro [gamma-32P]ATP-mediated labeling of this phosphorylation site was reduced to below detectable levels in td mutant nonproductively infected cell clones. These findings establish that the AbLV-encoded polyprotein P120 and its associated protein kinase activity are involved in AbLV tumorigenesis.
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PMID:Abelson murine leukemia virus transformation-defective mutants with impaired P120-associated protein kinase activity. 625 63


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