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Adenosine Monophosphate in the Early Transport Changes

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Adenosine Monophosphate in the Early Transport Changes Proc. Nat. Acad. Sci. USA Vol. 70, No. 12, Part I, pp. 3609-3612, December 1973 Role of Cyclic 3': 5 '-Adenosine Monophosphate in the Early Transport Changes Induced by Serum and Insulin in Quiescent Fibroblasts (uridine/phosphate/prostaglandins/tissue culture) ENRIQUE ROZENGURT* AND LUIS JIMENEZ DE ASUA* Department of Biological Sciences, Princeton University, Princeton, New Jersey 08540; and Imperial Cancer Research Fund Laboratories, Lincoln's Inn Fields, London, England Communicated by Arthur B. Pardee, July 23, 1973 ABSTRACT Serum or insulin added to quiescent Looking for a relationship between these early membrane mouse-embryo fibroblasts produced rapid increases in the changes, we found that the endogenous levels of cAMP rate of transport of uridine and phosphate and a decrease of the intracellular concentration of cyclic AMP. Incuba- dramatically affect the activation of uridine transport in- tion of the cells with prostaglandin E1, theophylline, or duced by serum or insulin. Addition or removal of prosta- both prevented the increase in uridine transport produced glandin E1 (PGE1) and theophylline brought about large and by serum or insulin. Prostaglandin E1 was more effective rapid transport changes that were associated with variations than prostaglandins E2 and B1. Kinetic experiments showed that the addition of prostaglandin E1 and theophylline in cAMP concentration. In contrast, phosphate uptake was causes the uridine transport rate to return to the basal not affected by the intracellular levels of cAMP. Thus, the level within 5 min; the rate rose rapidly after their removal. cyclic nucleotide is involved in the control of some specific Similar effects were obtained when insulin was used in- changes in membrane permeability. stead of serum. Associated with these transport changes were significant variations in the levels of cyclic AMP. MATERIALS AND METHODS An inverse correlation between the changes in uridine transport and those in cyclic AMP concentration was Secondary mouse-embryo fibroblasts were seeded in Dul- shown under various experimental conditions. In contrast becco's modified Eagle's medium supplemented with 0.2% to the effects observed with uridine transport, phosphate serum, 100 units/ml of penicillin, and 100 ug/ml of strepto- uptake was only slightly affected by changes in the endog- mycin in Nunc petri dishes. The cells were allowed to become enous level of cyclic AMP. We propose that at least two different sorts of membrane changes are rapidly initiated quiescent by incubating in this low-serum medium for at by serum, one under cyclic AMP control and the other not least 3 days before they were used. related to this nucleotide. Transport was measured with cells attached to 30-mm dishes. In most experiments, the medium was replaced by Quiescent cultures of untransformed fibroblasts recommence fresh serum-free medium with or without additions and after growth when serum is added. Selective increases in membrane 10 min, serum or insulin was added at a final concentration of permeability and changes in the intracellular concentration of 10% or 8 ug/ml, respectively. At the times indicated in each cyclic AMP (cAMP) are among the earliest events associated experiment the cells were exposed to labeled substrate for 5 with reinitiation of growth stimulated by addition of serum min and then washed four times with isotonic saline. Uptake (see ref. 1 for review). The rate of transport of uridine and into the acid-soluble fraction was measured by extracting the phosphae but not that of glucose and amino acids, is increased washed cells for 30 min at 40 with 5% trichloroacetic acid and several fold within 15 min after addition of serum to density- counting an aliquot in Triton-toluene scintillation fluid. inhibited 3T3 cells (2). cAMP, which is becoming implicated Cyclic AMP was determined by the binding competition increasingly in control of growth of fibroblasts (3-6), shows method described by Gilman (7), with cAMP binding protein opposite changes. A rapid fall in cAMP concentration was and protein kinase inhibitor from bovine muscle. The trichlo- found when serum or insulin was added to quiescent fibroblasts roacetic-acid extracts were purified by Dowex 50 chromatog- (4-6). Changes that occur earliest are of particular interest raphy as described (8). Treatment of samples prepared in in the search for triggering events and for cause and effect this way with cyclic nucleotide phosphodiesterase showed that connections between addition of serum and subsequent meta- the competing material was cAMP. Protein was determined bolic changes. by the method of Lowry et al. (9), after the attached cells The purpose of this paper is to investigate a possible role were washed five times with phosphate-buffered salt solution of cAMP in the early transport changes. The increases in up- (pH 7.2) take might be mediated by an indirect mechanism involving Nucleotides, theophylline, and cyclic nucleotide phospho- changes in the intracellular level of cAMP; conversely, the diesterase were obtained from Sigma. Crystalline insulin was transport changes might signal a modification of the mem- from Calbiochem. Prostaglandins were the generous gift of brane structure, that includes lower internal concentrations Dr. John Pike, Upjohn Co. Isotopically labeled compounds of cAMP; or the two phenomena could be unconnected. were obtained from The Radiochemical Center. Abbreviations: cAMP, cyclic 3': 5'-adenosine monophosphate; RESULTS PGE1, prostaglandin E1. Addition of serum to mouse-embryo fibroblasts made quies- * Present address: Imperial Cancer Research Fund, Lincoln's Inn cent by incubating in a low-serum medium brings about a 2- Fields, London, WC2, England. to 4-fold increase in uridine transport within 30 min. Pros- 3609 Downloaded by guest on October 2, 2021 3610 Biochemistry: Rozengurt and Jimenez de Asua Proc. Nat. Acad. Sci. USA 70 (1978) or insulin stimulation of uridine uptake (Fig. 2C and D). Experiments with exogenous cyclic nucleotides including dy- butyryl cyclic AMP were of limited value in this system be- cause 5'-AMP itself was inhibitory in the concentration range tested (0.2-1 mM). The kinetics of the changes in uridine uptake produced by addition or removal of PGE1 and theophylline in the presence of serum or insulin are shown in Fig. 3. A control without inhibitors shows that the rate of transport reached a maximum in 30 min. The addition of PGE1 plus theophylline before serum completely prevented the stimulatory effect of the latter. Removal of these compounds after 40 min of exposure was followed by a rapid recovery in transport which, however, was not complete (Fig. 3A). Conversely, when PGE1 and theophylline were added at different times after serum the 10 20 30 Prostaglandin yg/ml transport rate returned to the basal level in 5 min (Fig. 3B). Similar effects were obtained when insulin was used instead of FIG. 1. Effect of different prostaglandins on the serum-induced serum (Fig. 3C and D). increase in uridine transport. Prostaglandin El (0), prostaglandin cAMP levels were determined under conditions parallel E2 (0), and prostaglandin B1 (0) at the concentrations indicated, to those described for the kinetics of transport changes (Fig. were added 10 min before the fresh serum-free medium was sup- 4). Addition of serum to quiescent cultures reduced the in- plemented with serum. Some dishes were incubated with prostag- tracellular level of cAMP, as was reported for other cell lines landin El but without serum (A). The concentration of [3H] uridine (4-6). PGE, plus theophylline added 10 min before serum was 2.5 ACi/ml (29 Ci/mmol) and the cells were labeled (for 5 min) 30 min after addition of serum. Uptake into acid-soluble pool 8 (A) (B) was measured. All points represent averages of duplicate samples. la 6 ZIA V taglandin El added 10 min before serum preferentially in- a'A .v hibits the rise and was more effective than prostaglandins 'A~ v E2 and B1 (Fig. 1). Since all these prostaglandins activated 4 , ,_\v _# the adenylate cyclase activity of mouse-embryo fibroblasts A A 2 (10), the results suggest that cAMP is involved in the early 0 transport changes induced by serum. This possibility is fur- ther substantiated by the experiments shown in Fig. 2. 0 I 0 1 2 3 0 1 2 3 Theophylline, a well-known inhibitor of phosphodiesterase CL Theophylline ( mM ) activity, also inhibits the serum stimulation of uridine trans- co port in a concentration-dependent manner but does not de- (D) press the uptake rate in the absence of serum. This makes a ._ direct competitive effect of this compound on the uridine transport system unlikely. Insulin, which decreases the in- D mKZZ2 5, and see below), stimulated tracellular level of cAMP (4, 11, 50 uridine transport in the absence of serum. This stimulation 0f~ was completely inhibited by theophylline (Fig. 2B). Similar results were obtained when density-inhibited 3T3 cells were 0~~~~~~~~~~~~~~~- stimulated by serum or insulin. Furthermore, theophylline increased the effectiveness of PGE1 in preventing the serum I o 0 10 20 30,10 10 20 30 Prostaglandin (,ug/mI) TABLE 1. Effect of prostaglandin E1, theophylline, and El insulin on the cAMP levels of mouse-embryo fibroblasts FIG. 2. (A and B) Effect of different concentrations of theo- phylline on the serum (A)- or insulin (B)-induced increase in cAMP uridine transport. Theophylline was added 10 min before serum or Additions* (pmol/mg of protein) insulin (8,g/ml). Some dishes were incubated with theophylline but without serum or insulin (closed symbols). Transport rates are 22.7± 0.9 expressed as cpm X 10-3 per dish. (C and D). Potentiation by Insulin 14.3 ± 4 theophylline of the inhibition of uridine transport produced by Insulin + theophylline 27.5 ± 2.3 PGE,. Cells were incubated for 10 min with PGE1 (open symbols) PGE, 550 ± 14 or PGEI + theophylline (closed symbols) and then serum (C) or Insulin + PGE, 347 ± 27 insulin (D) was added.
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