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PMID: 6325469 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

Biochemical analysis of mutants of a macrophage cell line resistant to the growth-inhibitory activity of interferon.

The Journal of cell biology ·Vol. 98 ·No. 4 ·1984-04-00 ·Pages 1342-7

Nagata Y, Rosen OM, Makman MH, Bloom BR

Abstract

While a multiplicity of cellular and biochemical effects are mediated by interferons on cultured cells, the mechanisms involved in the direct growth-inhibitory activity of interferons remain problematic. We have previously found that variants in cAMP metabolism in a macrophage cell line, J774.2, were at least 50-fold less sensitive to the growth inhibitory activity of interferons (IFN) than the parental clone. To test the hypothesis that cAMP mediates the growth inhibition produced by IFN in these cells, interferon-resistant variants were selected and characterized with respect to cAMP synthesis and function. Approximately one-third of the IFN-resistant clones were found to be resistant to growth inhibition produced by cholera toxin, but not 8Br-cAMP. IFN was fully able to protect all of the interferon-resistant/choleratoxin-resistant (IFNr/CTr) clones against infection by vesicular stomatitis virus and markedly stimulated 2', 5'-oligodenylate synthetase activity. These IFNr/CTr variants were shown to have a defect in adenylate cyclase. The remaining IFN-resistant clones were fully susceptible to the growth-inhibitory effects of cholera toxin because their basal and stimulated adenylate cyclase activity is similar to that of the parental clone. IFN failed to protect these IFNr/choleratoxin sensitive clones against infection by vesicular stomatitis virus and failed to stimulate 2', 5-oligodenylate synthetase, suggesting that they have defective or deficient IFN receptors. In addition, IFN failed to increase intracellular cAMP levels in both IFNr/CTr and IFNr/choleratoxin sensitive clones. These results provide firm genetic and biochemical evidence that the growth inhibitory effects of IFN on this cell line are mediated by cAMP.

MeSH Terms
2',5'-Oligoadenylate Synthetase/metabolism Adenylyl Cyclases/metabolism Animals Cell Division/drug effects Cell Membrane/ultrastructure Clone Cells Cyclic AMP/metabolism Drug Resistance Genetic Variation Interferon Type I/toxicity Lymphoma, Large B-Cell, Diffuse Macrophages/drug effects,physiology Mice Mutation Vesicular stomatitis Indiana virus/drug effects
Chemicals
Interferon Type I Cyclic AMP 2',5'-Oligoadenylate Synthetase Adenylyl Cyclases
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Nagata Y
Rosen O M
Makman M H
Bloom B R
References (36)
36 references, click to expand
  1. Isolation of variants in phagocytosis of a macrophage-like continuous cell line.
    J Exp Med. 1977 Jan 1;145(1):175-86 PMID: 187717
  2. Effects of interferon on cell and virus growth in transformed human cell lines.
    J Gen Virol. 1976 Oct;33(1):7-15 PMID: 185329
  3. Mononuclear phagocytes: responders to and producers of interferon.
    Ann N Y Acad Sci. 1980;350:72-90 PMID: 6165307
  4. The use of the chemostat to study the relationship between cell growth rate, viability, and the effect of interferon on L 1210 cells.
    Exp Cell Res. 1979 Feb;118(2):383-8 PMID: 367800
  5. Effect of interferon on concentrations of cyclic nucleotides in cultured cells.
    Proc Natl Acad Sci U S A. 1979 Aug;76(8):3890-3 PMID: 226987
  6. Regulation of interferon action in human fibroblasts: transient induction of specific proteins and amplification of the antiviral response by antinomycin D.
    Virology. 1981 Jun;111(2):331-40 PMID: 6166117
  7. pppA2'p5'A2'p5'A: an inhibitor of protein synthesis synthesized with an enzyme fraction from interferon-treated cells.
    Proc Natl Acad Sci U S A. 1978 Jan;75(1):256-60 PMID: 272640
  8. Interferon assay based on the inhibition of double-stranded reovirus RNA accumulation in mouse L cells.
    J Gen Virol. 1973 Apr;19(1):81-7 PMID: 4360633
  9. Cyclic nucleotide-dependent protein kinases. IV. Widespread occurrence of adenosine 3',5'-monophosphate-dependent protein kinase in various tissues and phyla of the animal kingdom.
    Proc Natl Acad Sci U S A. 1969 Dec;64(4):1349-55 PMID: 4393915
  10. Somatic genetic analysis of cyclic AMP action: characterization of unresponsive mutants.
    J Cell Physiol. 1975 Jun;85(3):611-20 PMID: 167037
  11. Genetic approaches to the mechanism of macrophage functions.
    Fed Proc. 1978 Nov;37(13):2765-71 PMID: 213319
  12. Purified human immune interferon has more potent anticellular activity than fibroblast or leukocyte interferon.
    Cell Immunol. 1980 Feb;49(2):390-4 PMID: 6986204
  13. Abnormal behavior of interferon-induced enzymatic activities in an interferon-resistant cell line.
    Proc Natl Acad Sci U S A. 1980 Aug;77(8):4479-83 PMID: 6159629
  14. Genetic analysis of the role of cAMP in mediating effects of interferon.
    Proc Natl Acad Sci U S A. 1982 Mar;79(6):1879-83 PMID: 6177003
  15. Reticulum cell sarcoma: an effector cell in antibody-dependent cell-mediated immunity.
    J Immunol. 1975 Feb;114(2 pt 2):898-905 PMID: 1089721
  16. Isolation of an organ specific protein antigen from cell-surface membrane of rat liver.
    Biochim Biophys Acta. 1968 Apr 9;154(3):540-52 PMID: 4967807
  17. Interferon enhances 2-5A synthetase in embryonal carcinoma cells.
    Nature. 1979 Nov 1;282(5734):74-6 PMID: 503189
  18. Correction of defective macrophage differentiation in C3H/HeJ mice by an interferon-like molecule.
    J Immunol. 1982 Jan;128(1):380-7 PMID: 6172487
  19. Appearance of interferon inducibility and sensitivity during differentiation of murine teratocarcinoma cells in vitro.
    Cell. 1978 Feb;13(2):243-8 PMID: 627035
  20. Quantitative studies on viral interference in suspended L cells. III. Effect of interfering viruses and interferon on the growth rate of cells.
    Virology. 1962 Jun;17:324-34 PMID: 14484446
  21. Properties of protein kinase and adenylate cyclase-deficient variants of a macrophage-like cell line.
    J Cell Physiol. 1979 Jan;98(1):125-36 PMID: 216704
  22. A mutation affecting the catalytic subunit of cyclic AMP-dependent protein kinase in CHO cells.
    J Biol Chem. 1979 Aug 10;254(15):6931-7 PMID: 222748
  23. Enzymatic activities induced by interferon in human fibroblast cell lines differing in their sensitivity to the anticellular activity of interferon.
    Virology. 1981 May;111(1):11-22 PMID: 6165134
  24. Comparison of interferon action in interferon resistant and sensitive L1210 cells.
    J Gen Virol. 1978 Oct;41(1):161-6 PMID: 212514
  25. A highly sensitive adenylate cyclase assay.
    Anal Biochem. 1974 Apr;58(2):541-8 PMID: 4827395
  26. High-affinity binding of 125I-labelled mouse interferon to a specific cell surface receptor.
    Nature. 1980 Apr 3;284(5755):459-61 PMID: 6444699
  27. The ppp(A2'p)nA and protein kinase systems in wild-type and interferon-resistant Daudi cells.
    Eur J Biochem. 1982 Aug;126(2):333-41 PMID: 6181993
  28. Interferon action: two distinct pathways for inhibition of protein synthesis by double-stranded RNA.
    Proc Natl Acad Sci U S A. 1978 Dec;75(12):5893-7 PMID: 282611
  29. Interferon and cell division. I. Inhibition of the multiplication of mouse leukemia L 1210 cells in vitro by interferon preparations.
    Proc Natl Acad Sci U S A. 1970 Aug;66(4):1052-8 PMID: 4319881
  30. Protein measurement with the Folin phenol reagent.
    J Biol Chem. 1951 Nov;193(1):265-75 PMID: 14907713
  31. Metamorphosis of human amnion cells induced by preparations of interferon.
    Proc Natl Acad Sci U S A. 1961 Nov 15;47:1817-22 PMID: 13901742
  32. Antiviral and cell growth inhibitory activities reside in the same glycoprotein of human fibroblast interferon.
    Nature. 1976 Jul 22;262(5566):302-3 PMID: 958377
  33. A protein binding assay for adenosine 3':5'-cyclic monophosphate.
    Proc Natl Acad Sci U S A. 1970 Sep;67(1):305-12 PMID: 4318781
  34. Differential efficacies of human type I and type II interferons as antiviral and antiproliferative agents.
    Proc Natl Acad Sci U S A. 1980 Oct;77(10):5928-32 PMID: 6160587
  35. Inhibition of plasminogen activator secretion by cyclic AMP in a macrophage-like cell line.
    J Cyclic Nucleotide Res. 1978 Oct;4(5):345-58 PMID: 214471
  36. Interferon and cell division. IX. Interferon-resistant L1210 cells: characteristics and origin.
    J Natl Cancer Inst. 1974 Feb;52(2):553-9 PMID: 4856157
Article Info
Journal
The Journal of cell biology
Abbr.
J Cell Biol
ISSN
0021-9525
DOI
10.1083/jcb.98.4.1342
Published
1984-04-00
Pages
1342-7
Language
English
Region
United States
NLM ID
0375356
PMCID
PMC2113213
Subset
IM
Grants
NIAID NIH HHS · AI 07118 · United States
NIAID NIH HHS · AI 09807 · United States
NIAID NIH HHS · AI 10702 · United States
External Links
PubMed source DOI: 10.1083/jcb.98.4.1342 PMC Full Text View journal details
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