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Sphingosine-L-Phosphate, a Novel Lipid, Involved in Cellular Proliferation Hong Zhang, Naishadh N

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Sphingosine-L-Phosphate, a Novel Lipid, Involved in Cellular Proliferation Hong Zhang, Naishadh N Sphingosine-l-Phosphate, a Novel Lipid, Involved in Cellular Proliferation Hong Zhang, Naishadh N. Desai, Ana Olivera, Takashi Seki, Gary Brooker, and Sarah Spiegel* Department of Biochemistry and Molecular Biology, Georgetown University Medical Center, Washington, DC 20007 Abstract. Sphingosine, a metabolite of membrane elicited similar increases in sphingosine-l-phosphate sphingolipids, regulates proliferation of quiescent Swiss levels in these cells. Although both sphingosine and 3T3 fibroblasts (Zhang, H ., N. E. Buckley, K. Gibson, sphingosine-l-phosphate acted synergistically with a and S. Spiegel . 1990. J. Biol. Chem. 265:76-81) . The wide variety of growth factors, there was no additive or present study provides new insights into the formation synergistic effect in response to a combination of sphin- and function of a unique phospholipid, a metabolite of gosine and sphingosine-l-phosphate . Using a digital sphingosine, which was unequivocally identified as imaging system for measurement of calcium changes, sphingosine-l-phosphate . The rapid increase in 32P-la- we observed that both sphingosine and sphingosine-l- beled sphingosine-l-phosphate levels induced by sphin- phosphate are potent calcium-mobilizing agonists in gosine was concentration dependent and correlated with viable 3T3 fibroblasts. The rapid rise in cytosolic free its effect on DNA synthesis. Similar to the mitogenic calcium was independent of the presence of calcium in effects of sphingosine, low concentrations ofsphingosine- the external medium, indicating that the response is 1-phosphate stimulated DNA synthesis and induced due to the mobilization of calcium from internal stores. pronounced morphological alterations. Both sphingo- Our results suggest that sphingosine-l-phosphate may sine and sphingosine-l-phosphate stimulated DNA syn- be a component of the intracellular second messenger thesis in cells made protein kinase C deficient by pro- system that is involved in calcium release and the reg- longed treatment with phorbol ester and sphingosine still ulation of cell growth induced by sphingosine. HE biochemical mechanisms whereby eukaryotic cells tems involved in cell growth regulation have been elucidated regulate their proliferation are not well understood. (Berridge, 1985; Besterman et al ., 1986 ; Spiegel and Pana- One approach to this problem is to identify the second giotopoulos, 1988). In particular, it is clear that the early re- Tmessengers responsible for the initiation of the progression sponses ofquiescent cells to a variety ofgrowth factors, such of Góarrested cells into S phase. In Swiss 3T3 cells, which as changes in Cat+ and p1li , and activation of phospholipase are sensitive to a wide range of mitogenic agents, some C and protein kinase C, are insufficient by themselves to growth factors appear to function through conventional sec- cause the cells to progress to DNA synthesis (Hesketh et al., ond messengers such as cAMP, whereas others use the signal 1988). Thus, it appears that there are still some undiscovered pathways associated with increased degradation ofpolyphos- intracellular second-messenger pathways which are impor- phoinositides leading to the generation of lipid second mes- tant for cell growth regulation. sengers. Diacylglycerol (DAG)' is an endogenous activator Attention has recently been focused on other metabolites of protein kinase C (Nishizuka, 1986) and inositol trisphos- of membrane lipids, including phosphatidic acid (Exton, phate (IP3) causes a release ofCal+ from intracellular stores 1990; Moolenaar et al . 1986 ; Yu et al., 1988), arachidonic (Berridge, 1984; Berridge et al., 1984) . Although the roles acid, and prostaglandins and related derivatives (Needleman of these intracellular second messengers which appear to be et al., 1986) in signal transduction systems. A new addition important for the mitogenic response have been well charac- to this growing family of biologically active lipids emerged terized, it is evident that not all of the second messenger sys- from the discovery that sphingosine, a metabolite of mem- brane sphingolipids, inhibits protein kinase C, a pivotal Address correspondence to Dr. Sarah Spiegel, Departmentof Biochemistry regulatory enzyme in cell growth, opposing the action of and Molecular Biology, Georgetown University Medical Center, 357 Basic DAG (Hannun and Bell, 1989; Merrill and Stevens, 1989) . Science Building, 3900 Reservoir Road NW, Washington, DC 20007. Thus, it has been suggested that sphingosine may function as an endogenous negative effector ofprotein kinase C (Han- 1. Abbreviations used in this paper: DAG, diacylglycerol ; EGF, epidermal growth factor; fura-2/AM, fura-2/acetoxy-methyl ester; IP3, inositol tris- nun and Bell, 1989; Merrill and Stevens, 1989) . We have phosphate ; SPC, sphingosylphosphorylcholine ; TPA, 12-o-tetradecanoyl- shown previously that sphingosine stimulates the prolifera- phorbol 13-acetate . tion of quiescent Swiss 3T3 fibroblasts via a protein kinase © The Rockefeller University Press, 0021-9525/91/07/155/13 $2 .00 TheJournal of Cell Biology, Volume 114, Number 1, July 1991155-167 155 C-independent pathway (Zhang et al., 1990x). Recently, we Cell Culture have shown that the mitogenic effect of sphingosine is ac- Swiss 3T3 cells were from the American Type Culture Collection (CCL 92; companied by an increase in phosphatidic acid levels (Zhang Rockville, MD). Stock cultures of cells were routinely cultured as previ- et al ., 1990b), a potent mitogen for Swiss 3T3 cells (Yu et ously described (Spiegel, 1989x) . The cells were subcultured at a density al ., 1988; Moolenaar et al., 1986; Zhang et al., 1990b). of 1.5 x 10° cells/cm2 in DMEM supplemented with 2 mM glutamine, 1 This finding raises the possibility that sphingosine may play mM pyruvate, penicillin (100 U/ml), streptomycin (100 Wg/ml), and 10% FCS . For measurement of DNA synthesis, the cells were seeded and grown an important role as a positive regulator of cell growth acting on multicluster plastic tissue culture dishes (24 x 16-mm wells, Costar, through a novel pathway. A new action of sphingosine in Cambridge, MA). For phospholipid analysis, the cells were cultured in six- mediating rapid and profound translocation of Cal+ from well cluster plastic tissue culture dishes (6 x 34-mm wells, Costar Corp., 2+ intracellular stores has recently been described in permeabi- Cambridge, MA) . For measurements of cytoplasmic free Ca concentra- tion, cells were grown in lized smooth muscle cells (Ghosh et al ., 1990) . Ghosh et al . on glass cover slips six-well cluster plastic tissue culture dishes. The cells were refed with the same medium after 2 d and have proposed that sphingosine must be converted intracellu- were used 5 d later when the cells were confluent and quiescent (Spiegel larly to sphingosine-l-phosphate which affects calcium re- and Panagiotopoulos, 1988). lease from an intracellular calcium pool that includes the IP3-sensitive and -insensitive pools (Ghosh et al., 1990). In Assay ofDNA Synthesis this paper, we present evidence that sphingosine-l-phosphate Quiescent cultures were washed with DMEM to remove residual serum and is produced in viable cells in response to mitogenic stimula- 1 ml of DMEM/Waymouth medium (1 :1) supplemented with 20 Pg/ml BSA tion induced by sphingosine, is a potent mitogen for 3T3 fi- and 5 jig/ml transferrin were added (Spiegel and Panagiotopoulos, 1988 ; broblasts, and mediates calcium release . These results sug- Spiegel, 1989x) . When indicated, the cells were treated with variousgrowth gest that sphingosine-l-phosphate may be a component ofthe factors, sphingosine added as a complex with BSA (Zhang et al., 1990x), or sphingosine-l-phosphate, and after 18 h, the cells were pulsed with 0.5 intracellular second messenger system that is involved in cal- wCi of [3H]thymidine for 6 h. The incorporation of radioactivity into tri- cium release and the regulation of cell growth induced by chloroacetic acid-insoluble material was measured as described (Spiegel sphingosine . and Panagiotopoulos, 1988) . Values are the means of triplicate determina- tions. Standard deviations were routinely <10% of the mean . 32P Materials and Methods Labeling ofCells with ; Quiescent cultures of 3T3 cells were washed with DMEM without phos- Materials phate and incubated with 2 ml of this buffer containing 32p; (40 t Ci/ml) for 24 h. The cells were treated with sphingosine, or vehicle, or sphingosine-l- [Meth yl-3H]Thymidine (55 Ci/mmol), [32P]orthophosphate (carrier-free), phosphate alone for various times and the reactions were terminated by and [2- 3H]glycerol (1 Ci/mmol) were purchased from Amersham Chemi- placing the dishes on ice, and rapidly removing the medium . The cells were cal Corp. (Arlington Heights, IL). Epidermal growth factor (EGF), insulin, scraped from the dish in I ml of 0.1 N HCI . In some experiments, confluent and transferrin were from Collaborative Research (Lexington, MA). Phos- cultures were labeled with (23H)glycerol (2 ttCi/ml) for the last 3 d ofcul- pholipase D (from Streptomyces chromofuscus, type VI, 3,000 U/mg), 12- ture and 32p ; (40 t Ci/ml) was added for the final 24 h. Cells were rinsed O-tetradecanoylphorbol 13-acetate (TPA), D-sphingosine (from sphingo- with serum-free medium, and treated with sphingosine or vehicle and the myelin), and sphingosylphosphorylcholine (free base) were from Sigma lipids were extracted as described below. Chemical Co. (St . Louis, MO). The various standard phospholipids were from Avanti Polar Lipids
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