Skip to main content
NCBI home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1972 Oct;69(10):3024–3027. doi: 10.1073/pnas.69.10.3024

Guanosine 3′:5′-Cyclic Monophosphate: A Possible Intracellular Mediator of Mitogenic Influences in Lymphocytes

John W Hadden *,†, Elba M Hadden *, Mari K Haddox ‡, Nelson D Goldberg ‡
PMCID: PMC389699  PMID: 4342973

Abstract

Adenosine 3′:5′-cyclic monophosphate (cyclic AMP) has been shown to have an antimitotic role in various cell types, and it has been hypothesized that a decrease of cyclic AMP concentration in the cell initiates or permits cell division. This hypothesis has been evaluated with respect to clonal proliferation of lymphocytes. Two potent mitogenic agents, phytohemagglutinin and concanavalin A, which induce thymic-dependent lymphocytes to undergo clonal proliferation, were examined for their ability to initiate proliferation and to alter the concentrations of cyclic AMP and guanosine 3′:5′-cyclic monophosphate (cyclic GMP) in purified human peripheral blood-lymphocytes. Optimal mitogenic concentrations of phytohemagglutinin and concanavalin A produced 10- to 50-fold increases in the concentration of lymphocyte cyclic GMP within the first 20 min of exposure to the mitogens. No changes were seen in the concentration of cyclic AMP after stimulation with either mitogen in purified form. Increases of less than 2-fold in the concentration of lymphocyte cyclic AMP observed with a less purified preparation of phytohemagglutinin could be attributed to the agglutinating rather than the mitogenic properties of the mitogen. A revised hypothesis is presented in which a temporally discrete rise in lymphocyte cyclic GMP concentration is viewed as an active signal to induce proliferation, while the elevation of cyclic AMP concentration in these cells is viewed as a regulatory influence that limits or inhibits mitogenic action.

Keywords: phytohemagglutinin, concanavalin A, cyclic AMP, proliferation

Full text

PDF
3024

Selected References

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

  1. Adler W. H., Osunkoya B. O., Takiguchi T., Smith R. T. The interactions of mitogens with lymphoid cells and the effect of neuraminidase on the cells' responsiveness to stimulation. Cell Immunol. 1972 Apr;3(4):590–605. doi: 10.1016/0008-8749(72)90121-9. [DOI] [PubMed] [Google Scholar]
  2. George W. J., Polson J. B., O'Toole A. G., Goldberg N. D. Elevation of guanosine 3',5'-cyclic phosphate in rat heart after perfusion with acetylcholine. Proc Natl Acad Sci U S A. 1970 Jun;66(2):398–403. doi: 10.1073/pnas.66.2.398. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Gilman A. G. A protein binding assay for adenosine 3':5'-cyclic monophosphate. Proc Natl Acad Sci U S A. 1970 Sep;67(1):305–312. doi: 10.1073/pnas.67.1.305. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Greaves M. F., Bauminger S. Activation of T and B lymphocytes by insoluble phytomitogens. Nat New Biol. 1972 Jan 19;235(55):67–70. doi: 10.1038/newbio235067a0. [DOI] [PubMed] [Google Scholar]
  5. Hadden J. W., Hadden E. M., Good R. A. Adrenergic mechanisms in human lymphocyte metabolism. Biochim Biophys Acta. 1971 May 18;237(2):339–347. doi: 10.1016/0304-4165(71)90328-x. [DOI] [PubMed] [Google Scholar]
  6. Hadden J. W., Hadden E. M., Middleton E., Jr Lymphocyte blast transformation. I. Demonstration of adrenergic receptors in human peripheral lymphocytes. Cell Immunol. 1970 Dec;1(6):583–595. doi: 10.1016/0008-8749(70)90024-9. [DOI] [PubMed] [Google Scholar]
  7. Hirschhorn R., Grossman J., Weissmann G. Effect of cyclic 3',5'-adenosine monophosphate and theophylline on lymphocyte transformation. Proc Soc Exp Biol Med. 1970 Apr;133(4):1361–1365. doi: 10.3181/00379727-133-34690. [DOI] [PubMed] [Google Scholar]
  8. 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]
  9. Makman M. H. Properties of adenylate cyclase of lymphoid cells. Proc Natl Acad Sci U S A. 1971 May;68(5):885–889. doi: 10.1073/pnas.68.5.885. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Novogrodsky A., Katchalski E. Effect of phytohemagglutinin and prostaglandins on cyclic AMP synthesis in rat lymph node lymphocytes. Biochim Biophys Acta. 1970 Aug 14;215(2):291–296. doi: 10.1016/0304-4165(70)90027-9. [DOI] [PubMed] [Google Scholar]
  11. 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]
  12. Peters J. H., Hausen P. Effect of phytohemagglutinin on lymphocyte membrane transport. I. Stimulation of uridine uptake. Eur J Biochem. 1971 Apr 30;19(4):502–508. doi: 10.1111/j.1432-1033.1971.tb01341.x. [DOI] [PubMed] [Google Scholar]
  13. Pogo B. G., Allfrey V. G., Mirsky A. E. RNA synthesis and histone acetylation during the course of gene activation in lymphocytes. Proc Natl Acad Sci U S A. 1966 Apr;55(4):805–812. doi: 10.1073/pnas.55.4.805. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Quastel M. R., Kaplan J. G. Early stimulation of potassium uptake in lymphocytes treated with PHA. Exp Cell Res. 1970 Nov;63(1):230–233. doi: 10.1016/0014-4827(70)90360-5. [DOI] [PubMed] [Google Scholar]
  15. Sheppard J. R. Difference in the cyclic adenosine 3',5'-monophosphate levels in normal and transformed cells. Nat New Biol. 1972 Mar 1;236(61):14–16. doi: 10.1038/newbio236014a0. [DOI] [PubMed] [Google Scholar]
  16. 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]
  17. 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]
  18. Weber T., Nordman C. T., Gräsbeck R. Separation of lymphocyte-stimulating and agglutinating activities in phytohaemagglutinin (PHA) from Phaseolus vulgaris. Scand J Haematol. 1967;4(1):77–80. doi: 10.1111/j.1600-0609.1967.tb01601.x. [DOI] [PubMed] [Google Scholar]
  19. Winchurch R., Ishizuka M., Webb D., Braun W. Adenyl cyclase activity of spleen cells exposed to immunoenhancing synthetic oligo- and polynucleotides. J Immunol. 1971 May;106(5):1399–1400. [PubMed] [Google Scholar]
  20. Yachnin S., Allen L. W., Baron J. M., Svenson R. H. The potentiation of phytohemagglutinin-induced lymphocyte transformation by cell-cell interaction; a matrix hypothesis. Cell Immunol. 1972 Apr;3(4):569–589. doi: 10.1016/0008-8749(72)90120-7. [DOI] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES