Effect of Adenosine 3'-5'-Cyclic Monophosphate on Cell Proliferation

Froehlich, Jeffrey E.; Rachmeler, Martin

doi:10.1083/jcb.55.1.19

Cited by 140 publications

(31 citation statements)

References 34 publications

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“…7) the observation that administration of fresh serum to serum-restricted cultures causes a drop in cAMP (14,17,18,26). The rapidity of this drop compared with the slow rise in cAMP upon serum starvation is remarkable.…”

Section: Methodsmentioning

confidence: 99%

Intracellular Cyclic AMP Concentration Responds Specifically to Growth Regulation by Serum

Oey

Vogel

Pollack

1974

Proc. Natl. Acad. Sci. U.S.A.

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AB STRACTIntracellular concentrations of cyclic AMP increase when cells are deprived of serum. Studies with the mouse fibroblast line 3T3, an SV40-transformed subline of 3T3, and six different revertant lines derived from this clone show that a marked increase in cyclic AMP occurs only when the serum concentration is reduced below the minimum necessary for growth of a given line. Conversely, density-dependent inhibition of growth is not accompanied by an increase in cyclic AMP concentration in any line.The regulation of proliferation of fibroblast cultures is complex. Well regulated cell lines, such as the mouse line 3T3, are sensitive to inhibition by at least three different environmental signals: contact with other cells (1-3), deprivation of serum (4, 5), and absence of a solid substrate (6). SV40 virus transformed 3T3 clones may lose sensitivity to all three signals, and thus grow despite cell-cell contact (2), grow even when serum is reduced by 10-fold (7), and form spherical colonies when suspended in methyl cellulose gel (8, 9) ( Table 1). This loss of growth control can be reversed. By applying negative selection pressures to transformants, we have obtained cell lines, called revertants, which exhibit growth control comparable to that of normal cells (7, 9-11). Some revertants have regained sensitivity to contact-regulations and anchorage-regulations without regaining a high serum requirement for growth. We term these "density-revertants" (10, 11) ( Table 1). Other revertants have regained a high serum requirement for growth and, in addition, sensitivity to either contact alone, or to both contact and anchorage. We term these "serum-revertants" (7) ( Table 1).Many studies have suggested a possible inhibitory role for 3': 5'-cyclic AMP (cAMP) in the regulation of proliferation of fibroblast cultures (12-19). When cAMP is measured directly in cultures of normal and transformed cell lines, the concentration of cAMP is consistently found to be about half as high in growing cultures of transformed lines (13)(14)(15)(16)(17)

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Section: Methodsmentioning

confidence: 99%

Intracellular Cyclic AMP Concentration Responds Specifically to Growth Regulation by Serum

Oey

Vogel

Pollack

1974

Proc. Natl. Acad. Sci. U.S.A.

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“…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.…”

Section: Introductionmentioning

confidence: 99%

“…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)(7)(8)(9)(10). Proliferation of contact-inhibited cells, induced by refeeding or proteolytic treatment, is prevented by cAMP analogs (7,11).…”

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confidence: 99%

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Cyclic AMP, a nonessential regulator of the cell cycle.

Coffino

Gray

Tomkins

1975

Proc. Natl. Acad. Sci. U.S.A.

101

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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)

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“…162 production in the W138 cells (Kurtz et al, 1974;Kelly & Butcher, 1974;Makman et al, 1973). Froehlich & Rachmeler (1972) demonstrated that the addition of cyclic AMP or 6-N,2'-O-dibutyryl cyclic AMP inhibits cell division in human lung fibroblasts. We demonstrated that 8-methylthioadenosine 3': 5'-cyclic monophosphate (methylthio cyclic AMP), an analogue of cyclic AMP, has an effect very similar to that of PGE1 on the W138 cells in culture, in that it also inhibits cell division and the incorporation of [3H]thymidine into DNA (Polgar et al, 1975).…”

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confidence: 99%

Effects of prostaglandin on substrate uptake and cell division in human diploid fibroblasts

Polgár¹,

Taylor²

1977

Biochemical Journal

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PG (prostaglandin) El inhibits the uptake of uridine, thymidine, 2-deoxy-D-glucose and L-isoleucine into human diploid WI38 fibroblasts. The inhibition occurs within seconds of the addition of the prostaglandin to the culture. PGE2, PGFlm and PGF2. behave similarly. Arachidonic acid and 8,11,14-eicosatrienoic acid also decrease uptake in the presence or absence of indomethacin. Other unsaturated fatty acids such as oleic acid, linoleic acid and linolenic acid are essentially inactive. Ricinoleic acid (the 9-hydroxyoleic acid), however, inhibits uptake to about the same degree, at concentrations similar to those of the prostaglandins. Results indicate that this rapid blockage by the prostaglandins and certain fatty acids is not cyclic AMP-mediated. For example, although PGF1, and PGF2. are much poorer stimulators of cyclic AMP formation than are PGE1 and PGE2, they are nevertheless effective inhibitors of substrate uptake. Adrenaline, a very effective stimulator of cyclic AMP formation in the cells, is not inhibitory. Also, the addition of 8-methylthioadenosine 3': 5'-cyclic monophosphate (methylthio cyclic AMP) to the culture does not cause an immediate blockage of uptake. However, 22h after addition to the culture, methylthio cyclic AMP decreases the uptake of nucleotides into cultures undergoing active cell division, approximately to values found in quiescent cultures. PGE1 also has this effect on cells undergoing active growth. This gradual decrease in substrate uptake caused by PGE1 appears to be a separate event from its initial rapid inhibition of uptake.

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Effect of Adenosine 3'-5'-Cyclic Monophosphate on Cell Proliferation

Cited by 140 publications

References 34 publications

Intracellular Cyclic AMP Concentration Responds Specifically to Growth Regulation by Serum

Intracellular Cyclic AMP Concentration Responds Specifically to Growth Regulation by Serum

Cyclic AMP, a nonessential regulator of the cell cycle.

Effects of prostaglandin on substrate uptake and cell division in human diploid fibroblasts

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