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

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.The lymphocyte, a cell whose normal functions include, clonal proliferation after stimulation by antigen, provides a model for studying the biochemical events related to initiation of cellular division. Mitogens, such as phytohemagglutinin (PHA) and concanavalin A (Con A), have been used to induce clonal proliferation in lymphocytes, particularly those derived from the thymus. Several experiments (1-6) have been performed in which the relationship between cyclic AMP concentration and mitogen-induced lymphocyte division has been investigated. The results indicate (a) that cyclic AMP itself does not significantly stimulate division of lymphocytes in the resting phase ("Go" or "G1" phase) of the cell cycle (1), (b) that increases in cyclic AMP concentration resulting from stimulation by hormones and polynucleotides do not induce lymphocytes to divide (2, 3), and (c) that agents that promote increases in Iymphocyte cyclic AMP concentration inhibit mitogen-induced clonal proliferation (4-6).Abbreviations: PHA, phytohemagglutinin; Con A, concanavalin A.t To whom reprint requests should be addressed: Box 494 Mayo, University of Minnesota Hospitals, Minneapolis, Minn. 55455.In contrast to the foregoing is the observation that high concentrations of PHA can induce small increases in the amounts of cyclic AMP in lymphocytes (4). These observations have been interpreted as support for the concept that PHA exerts its mitogenic effects through an increase in cellular cyclic AMP concentration. Support for the o...

Effects of cholinergic agents and sodium ions on the levels of guanosine and adenosine 3′:5′‐cyclic monophosphates in neuroblastoma and neuroblastoma x glioma hybrid cells

“…This unexplained effect, which has also been observed in other systems [20,22,23,28,36] is the object of further studies in our laboratory.…”

“…It appears as if at the low concentration of Na ÷ the 'desensitized' state of the cholinergic receptor was more populated than at high Na ÷ concentration. Na+ enhances the binding of angiotensin to its receptor [36]. It also plays an important role in the action of opiates, although in comparison to the cholinergic agents the situation appears to be reversed.…”

Guanylate Cyclase : Assay and Properties of the Particulate and Supernatant Enzymes in Mouse Parotid

“…lectins [3] and cultured fibroblasts treated with fibroblast growth factor [5]. It also appears that cyclic GMP plays a role in cholinergic transmission and cholinergic agents raise the level of cyclic GMP in a wide variety of tissues [1,.…”

Immunohistochemical localization of 3': 5'-cyclic AMP and 3': 5'-cyclic GMP in rat liver, intestine, and testis.

“…In lymphocytes (4) and fibroblasts (5) cyclic GMP levels increase transiently after the addition of growth-promoting factors. While abundant evidence has accumulated which suggests that both cyclic AMP and cyclic GMP are involved in the regulation of the cell cycle, the mechanisms forsuch control have not been thoroughly determined.…”