c-AMP and the cell cycle: Inhibition of growth stimulation

Bombik, Bernd M.; Burger, Max M.

doi:10.1016/0014-4827(73)90278-4

Cited by 101 publications

(17 citation statements)

References 16 publications

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“…Cholera toxin, which acts through cAMP as a second messenger, improves cell growth and inhibits the differentiation-inducing activity of serum (Lechner 1984;Wu et al 1986). Several studies have shown that the levels of cAMP are inversely related to the rate of cell division, with high levels present in non-dividing cells (Otten et al 1972;Bombik and Burger 1973). In brain endothelial cells cAMP is a strong inducer of barrier functions (Deli et al 2005).…”

Section: Resultsmentioning

confidence: 99%

Retinoic acid and hydrocortisone strengthen the barrier function of human RPMI 2650 cells, a model for nasal epithelial permeability

et al. 2012

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The nasal pathway represents an alternative route for non-invasive systemic administration of drugs. The main advantages of nasal drug delivery are the rapid onset of action, the avoidance of the first-pass metabolism in the liver and the easy applicability. In vitro cell culture systems offer an opportunity to model biological barriers. Our aim was to develop and characterize an in vitro model based on confluent layers of the human RPMI 2650 cell line. Retinoic acid, hydrocortisone and cyclic adenosine monophosphate, which influence cell attachment, growth and differentiation have been investigated on the barrier formation and function of the nasal epithelial cell layers. Real-time cell microelectronic sensing, a novel label-free technique was used for dynamic monitoring of cell growth and barrier properties of RPMI 2650 cells. Treatments enhanced the formation of adherens and tight intercellular junctions visualized by electron microscopy, the presence and localization of junctional proteins ZO-1 and b-catenin demonstrated by fluorescent immunohistochemistry, and the barrier function of nasal epithelial cell layers. The transepithelial resistance of the RPMI 2650 cell model reached 50 to 200 X 9 cm 2 , the permeability coefficient for 4.4 kDa FITC-dextran was 9.3 to 17 9 10 -6 cm/s, in agreement with values measured on nasal mucosa from in vivo and ex vivo experiments. Based on these results human RPMI 2650 cells seem to be a suitable nasal epithelial model to test different pharmaceutical excipients and various novel formulations, such as nanoparticles for toxicity and permeability.

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Section: Resultsmentioning

confidence: 99%

Retinoic acid and hydrocortisone strengthen the barrier function of human RPMI 2650 cells, a model for nasal epithelial permeability

et al. 2012

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“…The rapidity of this drop compared with the slow rise in cAMP upon serum starvation is remarkable. This drop in cAMP is also inducible by proteases (18,19), insulin (27), and Somatomedin (28). Insulin and Somatomedin have been shown to act by inhibiting adenylate cyclase in the cell membrane (27,28), raising the hypothesis that serum stimulates growth through inhibition of membranebound adenylate cyclase.…”

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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“…These compounds strikingly potentiated the effect of cholera toxin on DNA synthesis and on cAMP levels. When quiescent Swiss 3T3 cells were exposed to cholera toxin (100 ng/ ml) and insulin at 10 pg/ml (4-to 7-fold increase in cAMP level) or to these agents and 1-methyl-3-isobutyl xanthine at 50 gIM (35-fold increase in cAMP level), DNA (6)(7)(8)(9)(10)). An objection to many ofthese studies has been that these effects were elicited by high concentrations of analogues of cAMP and could be regarded as nonspecific (2, 4).…”

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confidence: 99%

“…The possibility that the cyclic nucleotides, cyclic AMP (cAMP) and cyclic GMP, may.regulate the proliferative response of quiescent fibroblastic cells is the subject ofa large and controversial literature (2)(3)(4)(5). In 3T3 cells and other fibroblast cells, increased levels of cAMP are widely thought to reduce the rate ofgrowth and inhibit the stimulation of DNA synthesis promoted by adding serum to quiescent cells (6)(7)(8)(9)(10)). An objection to many ofthese studies has been that these effects were elicited by high concentrations of analogues of cAMP and could be regarded as nonspecific (2,4).…”

mentioning

confidence: 99%

Cyclic AMP: a mitogenic signal for Swiss 3T3 cells.

Rozengurt¹,

Legg²,

Strang³

et al. 1981

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

135

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Addition ofcholera toxin (100 ng/ml) to quiescent cultures of Swiss 3T3 cells acts synergistically with serum (2-4%), insulin, phorbol esters, epidermal growth factor, and fibroblastderived growth factor to stimulate DNA synthesis. In the presence of insulin, cholera toxin caused a dose-dependent increase in cumulative [3H]thymidine incorporation into acid-insoluble material and in the intracellular cyclic AMP (cAMP) level. The dose-response curves for the two processes were similar. Furthermore, addition of 1-methyl-3-isobutylxanthine (15-500 FLM) or of 4-(3-butoxy-4-methoxybenzyl)-2-imidazolidinone (5-100 gLM), both of which are potent inhibitors ofcyclic nucleotide phosphodiesterase activity, stimulated DNA synthesis and increased cAMP levels in Swiss 3T3 cells. These compounds strikingly potentiated the effect of cholera toxin on DNA synthesis and on cAMP levels. When quiescent Swiss 3T3 cells were exposed to cholera toxin (100 ng/ ml) and insulin at 10 pg/ml (4-to 7-fold increase in cAMP level) or to these agents and 1-methyl-3-isobutyl xanthine at 50 gIM (35-fold increase in cAMP level), DNA (6)(7)(8)(9)(10)). An objection to many ofthese studies has been that these effects were elicited by high concentrations of analogues of cAMP and could be regarded as nonspecific (2, 4). Furthermore, a few other studies with 3T3 cells suggested that cAMP promotes proliferation, but this contention remained unproven. Thus, addition of cAMP enhanced the initiation of DNA synthesis produced by serum, but noncyclic purine nucleotides or nucleosides were also effective (11). In addition, cholera toxin, an irreversible activator of the adenylate cyclase of eukaryote cells (12) was reported to stimulate, rather than inhibit, cell division in 3T3 cells maintained in-the presence of serum (13).However, the mitogenic effect of cholera toxin was not mimicked by other agents that elevated cAMP levels of 3T3 cells (13). All these inconsistent findings preclude any definitive conclusion concerning the effect ofcAMP on the initiation of DNA synthesis of fibroblast cell lines.A complicating factor in most early studies concerning the effect of cyclic nucleotides on the initiation of DNA synthesis is that they have been conducted in cultures maintained in nutrient medium supplemented with unfractionated serum. The complex nature ofserum and its multiplicity ofactions have frequently rendered difficult the interpretations of experiments with cultured animal cells grown in medium containing serum. In recent years, certain combinations of insulin, epidermal growth factor (EGF), vasopressin, phorbol esters, and fibroblast-derived growth factor (FDGF), a cell-derived growth factor, have been shown to completely replace serum in stimulating DNA synthesis in quiescent cultures of 3T3 cells (1, 14-16). We used such mitogenic factors and defined culture conditions to assess the effect ofcAMP elevating agents on the stimulation of DNA synthesis in cultures of Swiss 3T3 cells. In contrast to previous reports (2-10), we found that incr...

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c-AMP and the cell cycle: Inhibition of growth stimulation

Cited by 101 publications

References 16 publications

Retinoic acid and hydrocortisone strengthen the barrier function of human RPMI 2650 cells, a model for nasal epithelial permeability

Retinoic acid and hydrocortisone strengthen the barrier function of human RPMI 2650 cells, a model for nasal epithelial permeability

Intracellular Cyclic AMP Concentration Responds Specifically to Growth Regulation by Serum

Cyclic AMP: a mitogenic signal for Swiss 3T3 cells.

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