Skip to main content
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1978 Jan 1;147(1):171–181. doi: 10.1084/jem.147.1.171

Regulatory substances produced by lymphocytes. VI. Cell cycle specificity of inhibitor of DNA synthesis action in L cells

PMCID: PMC2184092  PMID: 203648

Abstract

IDS inhibits DNA synthesis and mitosis of L cells only when present during the late G1 phase of the cell cycle, as shown with L cells synchronized by a variety of methods. This corresponds well with earlier findings that IDS inhibits DNA synthesis in mitogen-stimulated lymphocytes when present between 16 and 24 h after adding mitogen. In both cell types, the inhibition produced by IDS appears to be totally the result of elevation of cAMP level. Thus, inhibitors of cAMP phosphodiesterase work synergistically with IDS, and activators of cAMP phosphodiesterase overcome the inhibition by IDS. This paper shows that IDS raises cAMP levels in L cells only within a narrow interval of the cell cycle, around 6-8 h after mitosis. This cell cycle specificity, which may be related to appearance of receptors for IDS only at discrete times, may be important in limiting IDS action to suppression, as elevated cAMP levels have a variety of other effects during other phases of the cell cycle.

Full Text

The Full Text of this article is available as a PDF (829.7 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bach J. F., Dardenne M., Pleau J. M., Bach M. A. Isolation, biochemical characteristics, and biological activity of a circulating thymic hormone in the mouse and in the human. Ann N Y Acad Sci. 1975 Feb 28;249:186–210. doi: 10.1111/j.1749-6632.1975.tb29068.x. [DOI] [PubMed] [Google Scholar]
  2. Brooks R. F. Regulation of fibroblast cell cycle by serum. Nature. 1976 Mar 18;260(5548):248–250. doi: 10.1038/260248a0. [DOI] [PubMed] [Google Scholar]
  3. Burger M. M., Bombik B. M., Breckenridge B. M., Sheppard J. R. Growth control and cyclic alterations of cyclic AMP in the cell cycle. Nat New Biol. 1972 Oct 11;239(93):161–163. doi: 10.1038/newbio239161a0. [DOI] [PubMed] [Google Scholar]
  4. Froehlich J. E., Rachmeler M. Effect of adenosine 3'-5'-cyclic monophosphate on cell proliferation. J Cell Biol. 1972 Oct;55(1):19–31. doi: 10.1083/jcb.55.1.19. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Greene W. C., Parker C. M., Parker C. W. Calcium and lymphocyte activation. Cell Immunol. 1976 Jul;25(1):74–89. doi: 10.1016/0008-8749(76)90098-8. [DOI] [PubMed] [Google Scholar]
  6. Jayawardena A. N., Waksman B. H. Suppressor cells in experimentally trypanosomiasis. Nature. 1977 Feb 10;265(5594):539–541. doi: 10.1038/265539a0. [DOI] [PubMed] [Google Scholar]
  7. Jegasothy B. V., Pachner A. R., Waksman B. H. Cytokine inhibition of DNA synthesis: effect on cyclic adenosine monophosphate in lymphocytes. Science. 1976 Sep 24;193(4259):1260–1262. doi: 10.1126/science.183266. [DOI] [PubMed] [Google Scholar]
  8. Leibovich S. J., Ross R. The role of the macrophage in wound repair. A study with hydrocortisone and antimacrophage serum. Am J Pathol. 1975 Jan;78(1):71–100. [PMC free article] [PubMed] [Google Scholar]
  9. Liacopoulos P., Ben-Efraim S. Antigenic competition. Prog Allergy. 1975;18:97–204. doi: 10.1159/000395257. [DOI] [PubMed] [Google Scholar]
  10. MacManus J. P., Whitfield J. F., Youdale T. Stimulation by epinephrine of adenyl cyclase activity, cyclic AMP formation, DNA synthesis and cell proliferation in populations of rat thymic lymphocytes. J Cell Physiol. 1971 Feb;77(1):103–116. doi: 10.1002/jcp.1040770112. [DOI] [PubMed] [Google Scholar]
  11. Macmanus J. P., Whitfield J. F. Stimulation of DNA synthesis and mitotic activity of thymic lymphocytes by cyclic adenosine 3'5'-monophosphate. Exp Cell Res. 1969 Nov;58(1):188–191. doi: 10.1016/0014-4827(69)90135-9. [DOI] [PubMed] [Google Scholar]
  12. Möller G., Lemke H., Opitz H. G. The role of adherent cells in the immune response. Fibroblasts and products released by fibroblasts and peritoneal cells can substitute for adherent cells. Scand J Immunol. 1976;5(3):269–280. doi: 10.1111/j.1365-3083.1976.tb00278.x. [DOI] [PubMed] [Google Scholar]
  13. Namba Y., Jegasothy B. V., Waksman B. H. Regulatory substances produced by lymphocytes. V. Production of inhibitor of DNA synthesis (IDS) by proliferating T lymphocytes. J Immunol. 1977 Apr;118(4):1379–1384. [PubMed] [Google Scholar]
  14. Namba Y., Waksman B. H. Regulatory substances produced by lymphocytes. II. Lymphotoxin in the rat. J Immunol. 1975 Oct;115(4):1018–1022. [PubMed] [Google Scholar]
  15. Otten J., Johnson G. S., Pastan I. Cyclic AMP levels in fibroblasts: relationship to growth rate and contact inhibition of growth. Biochem Biophys Res Commun. 1971 Sep;44(5):1192–1198. doi: 10.1016/s0006-291x(71)80212-7. [DOI] [PubMed] [Google Scholar]
  16. Pardee A. B. A restriction point for control of normal animal cell proliferation. Proc Natl Acad Sci U S A. 1974 Apr;71(4):1286–1290. doi: 10.1073/pnas.71.4.1286. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Pawelek J., Sansone M., Koch N., Christie G., Halaban R., Hendee J., Lerner A. B., Varga J. M. Melanoma cells resistant to inhibition of growth by melanocyte stimulating hormone. Proc Natl Acad Sci U S A. 1975 Mar;72(3):951–955. doi: 10.1073/pnas.72.3.951. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Puck T. T. Phasing, Mitotic Delay, and Chromosomal Aberrations in Mammalian Cells. Science. 1964 May 1;144(3618):565–566. doi: 10.1126/science.144.3618.565-c. [DOI] [PubMed] [Google Scholar]
  19. ROBBINS E., MARCUS P. I. MITOTICALLY SYNCHRONIZED MAMMALIAN CELLS: A SIMPLE METHOD FOR OBTAINING LARGE POPULATIONS. Science. 1964 May 29;144(3622):1152–1153. doi: 10.1126/science.144.3622.1152. [DOI] [PubMed] [Google Scholar]
  20. Rosenau W., Tsoukas C. D. Lymphotoxin. A review and analysis. Am J Pathol. 1976 Sep;84(3):580–596. [PMC free article] [PubMed] [Google Scholar]
  21. Rotter V., Trainin N. Increased mitogenic reactivity of normal spleen cells to T lectins induced by thymus humoral factor (THF). Cell Immunol. 1975 Apr;16(2):413–421. doi: 10.1016/0008-8749(75)90130-6. [DOI] [PubMed] [Google Scholar]
  22. Scheid M. P., Hoffmann M. K., Komuro K., Hämmerling U., Abbott J., Boyse E. A., Cohen G. H., Hooper J. A., Schulof R. S., Goldstein A. L. Differentiation of T cells induced by preparations from thymus and by nonthymic agents. J Exp Med. 1973 Oct 1;138(4):1027–1032. doi: 10.1084/jem.138.4.1027. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Sheppard J. R., Prescott D. M. Cyclic AMP levels in synchronized mammalian cells. Exp Cell Res. 1972 Nov;75(1):293–296. doi: 10.1016/0014-4827(72)90554-x. [DOI] [PubMed] [Google Scholar]
  24. Smith J. W., Steiner A. L., Newberry W. M., Jr, Parker C. W. Cyclic adenosine 3',5'-monophosphate in human lymphocytes. Alterations after phytohemagglutinin stimulation. J Clin Invest. 1971 Feb;50(2):432–441. doi: 10.1172/JCI106510. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Smith J. W., Steiner A. L., Parker C. W. Human lymphocytic metabolism. Effects of cyclic and noncyclic nucleotides on stimulation by phytohemagglutinin. J Clin Invest. 1971 Feb;50(2):442–448. doi: 10.1172/JCI106511. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. TERASIMA T., TOLMACH L. J. Growth and nucleic acid synthesis in synchronously dividing populations of HeLa cells. Exp Cell Res. 1963 Apr;30:344–362. doi: 10.1016/0014-4827(63)90306-9. [DOI] [PubMed] [Google Scholar]
  27. Tobey R. A., Anderson E. C., Petersen D. F. Properties of mitotic cells prepared by mechanically shaking monolayer cultures of Chinese hamster cells. J Cell Physiol. 1967 Aug;70(1):63–68. doi: 10.1002/jcp.1040700109. [DOI] [PubMed] [Google Scholar]
  28. Varga J. M., Dipasquale A., Pawelek J., McGuire J. S., Lerner A. B. Regulation of melanocyte stimulating hormone action at the receptor level: discontinuous binding of hormone to synchronized mouse melanoma cells during the cell cycle. Proc Natl Acad Sci U S A. 1974 May;71(5):1590–1593. doi: 10.1073/pnas.71.5.1590. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Wedner H. J., Parker C. W. Protein phosphorylation in human peripheral lymphocytes - stimulation by phytohemagglutinin and N6 monobutyryl cyclic AMP. Biochem Biophys Res Commun. 1975 Feb 17;62(4):808–815. doi: 10.1016/0006-291x(75)90394-0. [DOI] [PubMed] [Google Scholar]
  30. Willecke K., Ruddle F. H. Transfer of the human gene for hypoxanthine-guanine phosphoribosyltransferase via isolated human metaphase chromosomes into mouse L-cells. Proc Natl Acad Sci U S A. 1975 May;72(5):1792–1796. doi: 10.1073/pnas.72.5.1792. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. XEROS N. Deoxyriboside control and synchronization of mitosis. Nature. 1962 May 19;194:682–683. doi: 10.1038/194682a0. [DOI] [PubMed] [Google Scholar]
  32. Yoshida T., Bigazzi P., Cohen S. Biologic and antigenic similarity of virus-induced migration inhibition factor to conventional, lymphocyte-derived migration inhibition factor. Proc Natl Acad Sci U S A. 1975 Apr;72(4):1641–1644. doi: 10.1073/pnas.72.4.1641. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press

RESOURCES