A c-myc antisense oligodeoxynucleotide inhibits entry into S phase but not progress from G0 to G1 (original) (raw)

Nature volume 328, pages 445–449 (1987)Cite this article

Abstract

Initiation of T-lymphocyte proliferation by mitogen or antigen involves a cascade of gene activation events. Thus, by the time mitogen-activated T cells have reached the G1/S interface, many genes that are transcriptionally silent in GO, like the c-myc, IL-2, IL-2 receptor (IL-2R) and transferrin receptor (TfR) genes, have been transcriptionally activated1–4. To understand the role of the individual genes in the activation process, one must be able to interfere specifically with the expression or function of each particular gene product. In this way, by blocking the IL-2R with an antibody, it has been demonstrated that IL-2/IL-2R interaction is required to induce TfR expression in activated T cells3. When the function or expression of intracellular proteins is to be blocked, however, the need to introduce antibodies into the cytoplasm of viable cells, although possible5–7, is a limiting factor. We have taken another approach, namely the exogenous addition to bulk cell cultures of small antisense oligomers. Sequence-specific anti-sense oligodeoxyribonucleotides have been reported to inhibit intracellular viral replication without interfering with cellular protein synthesis8,9. Similarly, rabbit globin mRNA translation in a cell-free system and in rabbit reticulocytes has been inhibited by oligomers complementary to the globin mRNA initiation codon region10. Recently, a pentadecadeoxyribonucleotide complementary to the initiation codon and four downstream codons of human c-myc mRNA was reported to inhibit the proliferation of the human leukaemic cell line HL-60 specifically11. We report here that the same c-myc complementary oligonuelectide inhibits mitogen-induced c-myc protein expression in human T lymphocytes and prevents S phase entry. Interestingly, c-myc antisense treatment did not inhibit G0 to G1 traversal as assessed by morphologic blast transformation, transcriptional activation of the IL-2R and TfR genes, or induction of 3H-uridine incorporation.

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Authors and Affiliations

  1. Laboratory of Pathology, NC1, NIH, Bethesda, Maryland, 20892, USA
    Reino Heikkila, Gisela Schwab, Shee Loong Loke & Leonard M. Neckers
  2. Laboratory of Microbiology and Immunology, NIDR, NIH, Bethesda, Maryland, 20892, USA
    Dov H. Pluznik
  3. Departments of Chemistry, Biochemistry and Surgery, University of South Florida, Tampa, Florida, 33620, USA
    Eric Wickstrom
  4. Department of Molecular Genetics, Smith Kline and French Laboratories, Swedeland, Pennsylvania, 19479, USA
    Rosemary Watt

Authors

  1. Reino Heikkila
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  2. Gisela Schwab
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  3. Eric Wickstrom
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  4. Shee Loong Loke
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  5. Dov H. Pluznik
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  6. Rosemary Watt
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  7. Leonard M. Neckers
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Heikkila, R., Schwab, G., Wickstrom, E. et al. A c-myc antisense oligodeoxynucleotide inhibits entry into S phase but not progress from G0 to G1.Nature 328, 445–449 (1987). https://doi.org/10.1038/328445a0

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