Cyclic AMP, a nonessential regulator of the cell cycle.

Abstract

Flow-microfluorimetric analysis has been carried out on populations of exponentially growing S49 mouse lymphoma cells treated with dibutyryl cyclic AMP./The drug produces a specific concentration-dependent kblock in the GI phase of the cell cycle while other phases of the cycle are not perceptibly altered. The cell cycle of a line of mutant cells lacking the cyclic AMP-dependent protein kinase is not affected by the drug. Since these mutant cells have been shown to maintain a normal cell cycle, even in the presence of high levels of cyclic AMP, periodic fluctuations in the levels of the cyclic nucleotide cannot be required for or determine progression through the cell cycle.There is considerable evidence that adenosine 3': 5'-cyclic monophosphate (cAMP) has a regulatory effect on the growth of cells in culture. The levels of the cyclic nucleotide increase as untransformed cells approach confluency (1,2), although this is contradicted by others (3). Intracellular cAMP concentrations are negatively correlated with growth rate among a variety of fibroblast cell lines (4). Transformed cells have a lower cAMP content than untransformed cells (1, 5). Exogenous cAMP analogs or the induction of endogenous cAMP slows or stops growth of some cells (6-10). Proliferation of contact-inhibited cells, induced by refeeding or proteolytic treatment, is prevented by cAMP analogs (7,11). The cAMP level changes during the cell cycle and is specifically low in mitosis (11,12).While these results make it clear that cAMP can cause marked effects on the cell cycle, important questions remain unanswered.(i) Is cAMP merely a negative regulator of the cycle, or is variation of cellular cAMP levels a necessary signal that entrains the cell cycle? Burger et al. (11) have proposed, for instance, that a fall in cAMP is the signal that necessarily precedes DNA synthesis.(ii) What is the locus of the growth-inhibitory action of cAMP? This has been variously reported as lying in G1 (7,13,14), in G2 (8), or in multiple discrete portions of the cycle (15, 16). These studies have in most cases used cell populations synchronized by techniques that possibly cause unbalanced growth, which might raise questions regarding the use of these materials for examining the effect of a growth regulatory substance.To answer these questions we have studied growth regulation in cultured S49 mouse lymphoma cells. These cells are advantageous because growth of wild-type populations is inhibited by cAMP, and cAMP-insensitive mutants can be derived that are defective in the cAMP binding protein and its associated protein kinase (17,18). In the present studies we have used the flow-microfluorimeter (19)

Cell Cycle Regulation by Galectin-12, a New Member of the Galectin Superfamily

“…Cell Cycle Synchronization-Synchronization of Jurkat cells was performed by treatment of the cells (in logarithmic growth) overnight with 0.1 mM thymidine or 1 mM hydroxyurea to obtain cells at the G 1 /S boundary (48), with 0.1 g/ml nocodazole to block cells at mitosis, or with 0.2 mM theophylline plus 0.5 mM dibutyryl-cAMP to obtain cells at G 1 (49). RNA was extracted, and reverse transcription was done as described above.…”

“…Jurkat cells were treated with hydroxyurea or thymidine to synchronize cells at the G 1 /S boundary (48), with theophylline plus dibutyryl-cAMP to synchronize cells at G 1 (49), or with nocodazole to block cells at mitosis. As shown in Fig.…”

Oxytocin inhibits the proliferation of MDA-MB231 human breast-cancer cellsvia cyclic adenosine monophosphate and protein kinase A

“…cAMP can act as an inhibitor or a promoter of cell growth depending on cell type, cAMP concentration and specific gene induction (Sewen and Pouyssequz, 1992;Coffino et al, 1975;Starzec et al, 1994).…”

Revertants of an S49 cell mutant that expresses altered cyclic AMP-dependent protein kinase.

“…Induction of reversion by ICR191 suggests the existence of a novel mechanism for generating revertants in somatic cells. Adenosine 3',5'-phosphate (cAMP) inducers and analogs of cAMP cause growth inhibition (6) and cytolysis (8,9) in S49 mouse lymphoma tissue culture cells. We have utilized somatic cell genetics in an attempt to define the basis of cAMP action at the molecular level.…”