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Cell Cycle Regulation of Membrane Phospholipid Metabolism

Cell Cycle Regulation of Membrane Phospholipid Metabolism THE JOURNAL OF BIOLOGICAL CHEMISTRY Vol. 271, No. 34, Issue of August 23, pp. 20219–20222, 1996 Minireview © 1996 by The American Society for Biochemistry and Molecular Biology, Inc. Printed in U.S.A. the rate of PtdCho degradation decreased by an order of mag- Cell Cycle Regulation of nitude in S phase and then accelerated again as the cells Membrane Phospholipid entered the next G period, thereby establishing that PtdCho turnover in G was associated with the cell cycle and not a Metabolism* property of the G to G transition (12). The cessation of Ptd- 0 1 Cho degradation in S phase is likely an important contributor Suzanne Jackowski‡ to the net accumulation of phospholipid during this time; how- From the Department of Biochemistry, St. Jude ever, nothing is known about the biochemical processes that Children’s Research Hospital, Memphis, Tennessee govern the periodicity of PtdCho turnover. 38101 and the University of Tennessee, PtdCho turnover may be an important aspect of phospholipid Memphis, Tennessee 38163 metabolism during G that is necessary, and in some cases, sufficient for entry into S phase. PtdCho hydrolysis by phos- This review focuses on the phospholipid metabolism regu- pholipase C and/or D pathways is triggered by a wide array of lated by the cell cycle. Phospholipids are the major cellular agonists (9), and both exogenous bacterial PtdCho phospho- constituents required for the assembly of biological mem- lipase C (13) and PtdCho phospholipase D (14) added to the branes, and cells must double their phospholipid mass to form medium mimicked the mitogenic effect of platelet-derived daughter cells. It seems reasonable that this event should growth factor. The fact that PtdCho phospholipase C, like coincide with the synthesis of other cellular components such growth factors, was required throughout G for maximal mito- as DNA, stable RNA, etc.; however, the biochemical mecha- genic effect (15) supports a causal relationship between PtdCho nisms that coordinate macromolecular and bulk membrane turnover and G progression. The precise signal transduction phospholipid production are largely unknown. The importance pathways activated by PtdCho phospholipase C remain to be of these regulatory processes to cell physiology is obvious. Dis- clarified, although activation of the Ras-Raf pathway (16, 17) cordant regulation of phospholipid accumulation by only a few and/or protein kinase Cz (18) may be involved. percent per cell cycle would rapidly result in cells with either a large excess or deficit of membrane surface leading to abnor- S Phase malities in cell size and/or intracellular lipid accumulation. The net accumulation of phospholipid is a periodic event Thus, stringent control mechanisms must be in place to keep associated with S phase of the cell cycle. The first experiments the phospholipid content in tune with the cell cycle. This dis- established that phospholipid synthesis occurred during inter- cussion will explore the state of our knowledge in cultured phase as opposed to mitosis (19, 20). Subsequent measure- mammalian cell systems, although cell cycle-regulated phos- ments of the amount of phospholipid per cell during the first pholipid accumulation occurs in lower eukaryotes such as Sac- 12 h after mitogenic stimulation revealed little increase, charomyces cerevisiae (1) and Caulobacter crescentus (2). This whereas there was a significant rise in cellular phospholipid review is limited to a discussion of events that are directly tied content between 12 and 24 h (21, 22). In these studies, the first to the cell cycle. Phospholipid metabolism in response to mito- 12 h corresponded to the exit from G together with the G 0 1 genic stimulation will not be addressed as these biochemical phase of the cell cycle, whereas the time between 12 and 24 h events are generally associated with the G to G transition corresponded to S, G , and M phases. A more detailed analysis 0 1 and are ligand-regulated rather than being orchestrated by the revealed that phospholipid content doubled specifically during cell cycle. S phase (12, 20). This pattern of net phospholipid accumulation was consistent among a number of mammalian cell types in- G Phase cluding fibroblasts (21), HeLa cells (19), macrophages (12), The G phase of the cell cycle is characterized as having a 1 mast cells (20), and thymocytes (22). A key experiment was to high rate of membrane phospholipid turnover. Increased incor- follow the pattern of phospholipid accumulation through the poration of label into phospholipids and elevated levels of in- second cell cycle following synchronization to convincingly dis- tracellular soluble phospholipid precursors were noted after tinguish that membrane phospholipid acquisition was a cell the mitogenic stimulation of cells (3, 4), although these studies cycle-regulated process rather than a growth factor-triggered did not address whether the increase in labeling represented event that took several hours to initiate (12). The distribution net phospholipid synthesis or enhanced phospholipid turnover of major phospholipid classes in whole cells was essentially (5–11). Jackowski (12) examined both synthesis and degrada- constant throughout the cell cycle in NIH fibroblasts (11). Like- tion in a macrophage cell line using a double label experiment wise, the content of PtdIns, PtdIns-P, and PtdIns-P was rela- and attributed the increase in choline incorporation into Ptd- tively constant during the cell cycle (23), although specific Cho during G (4) to rapid PtdCho turnover (12). Importantly, changes have been observed in the nuclear compartment (see below). Net phospholipid accumulation is coordinated with S phase * This minireview will be reprinted in the 1996 Minireview Compen- dium, which will be available in December, 1996. This work was sup- of the cell cycle, but phospholipid synthesis is not dependent on ported by United States Public Health Service Grant GM45737 from DNA synthesis. Cell cycle arrest of a macrophage cell line in NIGMS, Cancer Center (CORE) Support Grant CA21765, and the mid-G with dibutyryl-cAMP or at the G /S boundary with 1 1 American and Lebanese Syrian Associated Charities. aphidicolin prevented S phase DNA synthesis; however, net ‡ To whom correspondence should be addressed: Biochemistry Dept., St. Jude Children’s Research Hospital, 332 N. Lauderdale, Memphis, phospholipid accumulation continued (12). These data illus- TN 38101. trated that the decision to double the phospholipid mass was The abbreviations used are: PtdCho, phosphatidylcholine; PtdEtn, phosphatidylethanolamine; PtdIns, phosphatidylinositol; PtdIns-P, phosphatidylinositol 4-phosphate; PtdIns-P , phosphatidylinositol 4,5- bisphosphate; CT, CTP:phosphocholine cytidylyltransferase. This is an open access article under the CC BY license. 20219 20220 Minireview: Phospholipids and the Cell Cycle made in early G , or perhaps M phase of the previous cell cycle, nase C, which, in turn, has been found to phosphorylate and and proceeded concurrently, but independently, of DNA repli- activate DNA polymerase and topoisomerase (30, 38). York et cation. The nature of the signal that licenses the cell to double al. (39) demonstrated the existence of a nuclear inositol polyphosphate-1-phosphatase. The overexpression of this ino- its membrane phospholipid mass is unknown but is likely to involve the expression or modification of key regulators in early sitol polyphosphate-1-phosphatase inhibited DNA synthesis, thus providing compelling evidence for inositol polyphosphates G . The overall phospholipid composition of isolated nuclei is not as determinants in the control of DNA synthesis. One likely candidate for nuclear signaling is inositol 1,4-bisphosphate markedly different from the whole cell; PtdCho, PtdEtn, and since this compound could bind to DNA polymerase and en- sphingomyelin are the predominant phospholipid species, and hance the affinity of the enzyme for DNA template/primer (40). PtdIns and its phosphorylated derivatives are represented as Alternatively, the identification of an inositol 1,4,5-trisphos- minor components (see Ref. 24 and references therein). Inter- phate receptor in the inner nuclear membrane that mediated estingly, nuclear phospholipids appear to be distributed within calcium release into the cytoplasm (41) indicated that inositol the interphase nucleus in addition to their presence in the polyphosphates played a role in regulating nuclear calcium nuclear membrane. Amorphous lipoprotein complexes were concentration, which in turn could influence DNA replication identified morphologically in the interphase cell nucleus, local- and gene transcription (42). Establishing the critical nuclear ized mainly in the interchromatin spaces and in the nucleolar target(s) and determining their function in the initiation and domain. Furthermore, a decrease in the overall nuclear phos- control of S phase DNA replication will be an interesting pholipid content was associated with DNA replication (25); challenge. however, the morphological analysis did not reveal whether this decrease was due to the disappearance of a specific phos- G and M Phases pholipid class. The apparent co-localization of phospholipids Much less is known about phospholipid metabolism in G and ribonucleoproteins suggested a role for phospholipid in the and M phases. There was little overall phospholipid synthesis mechanism of transport and release of transcripts. For exam- or degradation occurring in these latter stages based on meta- ple, the release of ribonucleoproteins after phospholipase A bolic labeling of macrophage cells synchronized by growth fac- digestion of the nucleus indicated that phospholipids may me- tor withdrawal (12). The paucity of information is due in part to diate the binding between ribonucleoprotein and the nuclear the difficulty in analyzing pure populations of cells in these matrix (24). The importance of these morphological observa- phases of the cell cycle. The G and S phases are between 6 and tions to the biochemical events taking place in the nucleus is a 12 h in length making it relatively easy to isolate adequate challenging area for future research. numbers of cells. However, the G /M phases are considerably Nuclear inositol phospholipid metabolism is a significant S shorter (2–4 h), and synchronous cell populations in G /M are phase-specific event. The enzymes of polyphosphoinositide contaminated with cells in S and G phases. Nocodazole is an turnover occur in the nucleus (for review see Ref. 26), and there effective agent that arrests cells in M phase; however, the use is considerable evidence for PtdIns-P synthesis (27, 28) and of cell cycle blockers can be problematic without corroboration degradation in the nuclear matrix (29–31). Nuclear PtdIns, from experiments with synchronous or elutriated cells. PtdIns-P, and PtdIns-P decreased coincident with S phase in The most significant event involving phospholipids in M HeLa cells (23), and the levels of all of the inositol phosphates phase is the cessation of membrane trafficking concomitant increased at both the G /S boundary and in S phase in the with the destruction and reassembly of the nuclear membrane nucleus of synchronized neuroblastoma cells (32). These data (43). While the dynamic aspects of the assembly of nuclear suggested that the PtdIns cycle was activated in S phase nuclei membrane protein components have received considerable ex- and implied the presence of a nuclear PtdIns-P phospholipase perimental attention (44), the phospholipid components have C that was specifically regulated during S phase. Phospho- not been studied in detail. Metabolic labeling of Chinese ham- lipase Cb1 is present in the nuclei of Swiss 3T3 cells and was ster ovary cells indicated that at least 50% of the nuclear postulated to be involved in the rapid responses of quiescent envelope phospholipid present in G was used to resynthesize (G ) cells stimulated to enter G by insulin growth factor-1 (33). 0 1 the nuclear envelopes of the daughter cells (45). Studies with More recently, Asano et al. (34) purified a novel phospholipase Amoeba proteus are worthy of mention because of their unique C isozyme that was only detected in the nuclei of regenerating approach (46). Autoradiographic observations following im- rat liver. Subsequently, a new isoform of PtdIns-specific phos- plantation of [ H]choline-labeled nuclei into unlabeled cells pholipase C (Cd4) was cloned, purified, and characterized by revealed little turnover of nuclear membrane phospholipid dur- two laboratories (35, 36). Importantly, phospholipase Cd4 was ing interphase; however, during mitosis the label was dis- primarily present in the nucleus, dramatically increased at the persed throughout the cytoplasm coincident with the degrada- G /S transition, and virtually disappeared by the time cells tion of the nuclear envelope. The cytoplasmic label was re-entered the next G phase (36). Thus, phospholipase Cd4 has subsequently divided equally among the daughter cell nuclei. the biological properties anticipated for the enzyme that regu- These data indicated that the nuclear envelope was recon- lates nuclear phosphoinositide metabolism during S phase, and structed from pre-existing phospholipids as the cells exited M it will be important to determine if its activity is regulated by phase and entered early G . The role of phospholipid trafficking cell cycle-specific expression alone or whether there is an ad- in the dissolution and reformation of the nuclear envelope ditional level of activity regulation by cyclin-dependent protein promises to be an exciting area for future investigation. kinases. Biochemical Mechanisms The products of polyphosphoinositide breakdown are thought to play a role in DNA synthesis, consistent with their The search for the biochemical mechanism underlying the formation during S phase. Treatment of the nuclear matrix periodic accumulation of membrane phospholipid has focused with phospholipase C released nucleic acid suggesting that on the control of PtdCho synthesis and degradation. PtdCho is polyphosphoinositides mediated the association of DNA with not only the most abundant membrane phospholipid, but it is the matrix (37), an interaction that may have to be disrupted also serves as the precursor for the other two predominant for efficient DNA synthesis. Alternatively, the diacylglycerol phospholipid species, PtdEtn (47) and sphingomyelin (48). released by phospholipase C may activate nuclear protein ki- Most cells are capable of synthesizing PtdEtn via CTP:phos- Minireview: Phospholipids and the Cell Cycle 20221 phoethanolamine cytidylyltransferase and ethanolamine phos- photransferase; however, tissue culture media lack ethanola- mine. Therefore, the CDP-ethanolamine pathway cannot contribute to bulk membrane formation in tissue culture sys- tems although it is likely to be important in PtdEtn turnover (49). CT is a key regulatory enzyme in PtdCho biosynthesis and hence phospholipid formation (50). CT is extensively phospho- rylated on its carboxyl-terminal domain in vivo (51), and CT phosphorylation is associated with the inhibition of enzyme activity (12, 52). Importantly, the extent of CT phosphorylation fluctuates with the cell cycle, and maximum CT phosphoryla- tion occurs in the G /M phase and correlates with the cessation of phospholipid synthesis (12). Nuclear CT (53–56, 68) is in the correct subcellular compartment for regulation by cyclin-de- pendent kinases, and the observation that CT is phosphoryl- ated to some extent in vitro by Cyclin B/Cdc2 kinase (57, 69) suggests that the regulators of the cell cycle control the pace of FIG.1. Relationship between phospholipid metabolism and phospholipid synthesis through the direct phosphorylation of the cell cycle. G phase is characterized by a high rate of PtdCho degradation and resynthesis that is dependent on growth factor and CT. However, CT activity regulation by cyclin-dependent pro- terminates at the G /S boundary. Doubling of the phospholipid mass tein kinase phosphorylation has not been directly demon- occurs in S phase due to continued phospholipid synthesis but with strated, and there are likely to be additional enzymes (i.e. those drastically reduced phospholipid turnover. The turnover of nuclear responsible for PtdCho degradation) that contribute to the ob- polyphosphoinositides is an additional S phase event that may be a component of a regulatory network that governs DNA replication. The served periodicity in membrane formation. Identifying these G and M phases are characterized by the cessation of phospholipid enzymes and their modes of regulation is obviously important metabolism. to completing the understanding of cell cycle regulation of phospholipid metabolism. phospholipid accumulation and the inhibition of phospholipid Do Lipids Regulate the Cell Cycle? synthesis did not have an immediate impact on DNA replica- tion (63). S phase is also associated with the turnover of nuclear While it is apparent that the cell cycle controls bulk phos- pholipid and membrane biogenesis, it is not clear whether the polyphosphoinositides that generate messengers thought to be components of DNA replication. G and M phases are charac- cell cycle is in turn influenced by lipid content. Several studies reported that the inhibition of fatty acid and/or phospholipid terized by a cessation of phospholipid metabolism where both synthesis and degradation of membrane lipid components synthesis by nutritional deprivation (i.e. biotin or choline star- reach their nadir. This conceptual model serves as the spring- vation) led to the accumulation of several cell types in G board for launching future investigation into the underlying (58–61). When C3H/10T1/2 fibroblasts were deprived of cho- biochemical mechanisms. line and synchronized in G by incubation in low serum, the Virtually nothing is known about the key regulatory en- cells did not efficiently enter S phase following serum restimu- zymes or the biochemical mechanisms employed during the cell lation suggesting that PtdCho synthesis was a requirement for cycle to generate the periodic pattern of phospholipid metabo- S phase entry (61). However, cells deprived of choline contin- lism. Cell cycle regulation is governed by the activity of cyclin- ued to divide for several days (61), and Chinese hamster ovary dependent protein kinases (64–66); therefore, it seems likely cells with a temperature-sensitive defect in CT activity contin- that these kinases either directly or indirectly deliver regula- ued to grow for several doublings in the absence of PtdCho tory signals to key enzymes in phospholipid biosynthesis. One synthesis via the de novo pathway (62). These latter data of the most interesting remaining questions is how does the suggest that proliferating cells do not detect phospholipid con- phospholipid biosynthetic apparatus obtain a license to double tent as a determinant of cell cycle progression. However, ex- the membrane phospholipid mass? This permit is issued in amining the state of cyclins and their associated kinases in early G since blocking the cell cycle in either mid-G or at the cells arrested by choline starvation or in the temperature- 1 1 G /S boundary does not prevent doubling of the phospholipid sensitive CT mutants may reveal a relationship between phos- mass. Cyclin D-dependent protein kinases are the first cell pholipid metabolism and cell cycle control that is not apparent cycle-regulated kinases to appear in G (65) making them can- from these experiments. Alternatively, the accumulation of didate regulators of membrane phospholipid licensing. The ces- cells deficient in phospholipid in G may reflect a requirement sation of rapid PtdCho turnover at the G /S boundary contrib- for the high degradation or turnover of PtdCho that occurs utes to the accumulation of phospholipid in S phase. Cyclin during this phase of the cell cycle, which in turn demands an E/Cdk2 and Cyclin A/Cdk2 are two candidate cyclin-dependent accelerated rate of lipid synthesis. protein kinases that are expressed in late G and early S phase Concluding Remarks that may be regulators of PtdCho turnover by phosphorylating The experiments to date lead to a conceptual model for the and inhibiting the responsible enzyme(s). Alternatively, Ptd- modulation of phospholipid metabolism during the cell cycle Cho turnover may be positively regulated by growth factor (Fig. 1). The G phase is characterized by rapid synthesis and signaling. For example, colony-stimulating factor 1 was re- degradation of PtdCho that continues up to the G /S boundary. quired through most of G in order for macrophage cells to 1 1 PtdCho metabolism is so rapid that some cells turn over about enter S phase (67) and also stimulate PtdCho turnover (15). 75% of their total PtdCho during G . In S phase, PtdCho Therefore, the cessation of growth factor signaling in late G 1 1 turnover ceases, and the cells double their membrane phospho- may account for the concomitant cessation of PtdCho turnover. lipid content in preparation for cell division. Although DNA It will also be important to determine if nuclear phospholipase replication and expansion of the membrane phospholipid pool Cd4, polyphosphoinositol phosphatases, and PtdIns kinases are are coordinated with the cell cycle, they are not dependent on regulated by the cyclin-dependent protein kinases that are each other since inhibition of DNA replication did not block required for cells to initiate and traverse S phase. Finally, 20222 Minireview: Phospholipids and the Cell Cycle Biophys. Res. Commun. 218, 182–186 phospholipid synthesis reaches its nadir in the G and M 28. Cocco, L., Gilmour, R. S., Ognibene, A., Letcher, A. J., Manzoli, F. A., and phases, a stage characterized by the activation of Cyclin Irvine, R. F. 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Cell Cycle Regulation of Membrane Phospholipid Metabolism

Jackowski, Suzanne
Journal of Biological Chemistry – Aug 1, 1996
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Abstract

THE JOURNAL OF BIOLOGICAL CHEMISTRY Vol. 271, No. 34, Issue of August 23, pp. 20219–20222, 1996 Minireview © 1996 by The American Society for Biochemistry and Molecular Biology, Inc. Printed in U.S.A. the rate of PtdCho degradation decreased by an order of mag- Cell Cycle Regulation of nitude in S phase and then accelerated again as the cells Membrane Phospholipid entered the next G period, thereby establishing that PtdCho turnover in G was associated with the cell cycle and not a Metabolism* property of the G to G transition (12). The cessation of Ptd- 0 1 Cho degradation in S phase is likely an important contributor Suzanne Jackowski‡ to the net accumulation of phospholipid during this time; how- From the Department of Biochemistry, St. Jude ever, nothing is known about the biochemical processes that Children’s Research Hospital, Memphis, Tennessee govern the periodicity of PtdCho turnover. 38101 and the University of Tennessee, PtdCho turnover may be an important aspect of phospholipid Memphis, Tennessee 38163 metabolism during G that is necessary, and in some cases, sufficient for entry into S phase. PtdCho hydrolysis by phos- This review focuses on the phospholipid metabolism regu- pholipase C and/or D pathways is triggered by a wide array of lated by the cell cycle. Phospholipids are the major cellular agonists (9), and both exogenous bacterial PtdCho phospho- constituents required for the assembly of biological mem- lipase C (13) and PtdCho phospholipase D (14) added to the branes, and cells must double their phospholipid mass to form medium mimicked the mitogenic effect of platelet-derived daughter cells. It seems reasonable that this event should growth factor. The fact that PtdCho phospholipase C, like coincide with the synthesis of other cellular components such growth factors, was required throughout G for maximal mito- as DNA, stable RNA, etc.; however, the biochemical mecha- genic effect (15) supports a causal relationship between PtdCho nisms that coordinate macromolecular and bulk membrane turnover and G progression. The precise signal transduction phospholipid production are largely unknown. The importance pathways activated by PtdCho phospholipase C remain to be of these regulatory processes to cell physiology is obvious. Dis- clarified, although activation of the Ras-Raf pathway (16, 17) cordant regulation of phospholipid accumulation by only a few and/or protein kinase Cz (18) may be involved. percent per cell cycle would rapidly result in cells with either a large excess or deficit of membrane surface leading to abnor- S Phase malities in cell size and/or intracellular lipid accumulation. The net accumulation of phospholipid is a periodic event Thus, stringent control mechanisms must be in place to keep associated with S phase of the cell cycle. The first experiments the phospholipid content in tune with the cell cycle. This dis- established that phospholipid synthesis occurred during inter- cussion will explore the state of our knowledge in cultured phase as opposed to mitosis (19, 20). Subsequent measure- mammalian cell systems, although cell cycle-regulated phos- ments of the amount of phospholipid per cell during the first pholipid accumulation occurs in lower eukaryotes such as Sac- 12 h after mitogenic stimulation revealed little increase, charomyces cerevisiae (1) and Caulobacter crescentus (2). This whereas there was a significant rise in cellular phospholipid review is limited to a discussion of events that are directly tied content between 12 and 24 h (21, 22). In these studies, the first to the cell cycle. Phospholipid metabolism in response to mito- 12 h corresponded to the exit from G together with the G 0 1 genic stimulation will not be addressed as these biochemical phase of the cell cycle, whereas the time between 12 and 24 h events are generally associated with the G to G transition corresponded to S, G , and M phases. A more detailed analysis 0 1 and are ligand-regulated rather than being orchestrated by the revealed that phospholipid content doubled specifically during cell cycle. S phase (12, 20). This pattern of net phospholipid accumulation was consistent among a number of mammalian cell types in- G Phase cluding fibroblasts (21), HeLa cells (19), macrophages (12), The G phase of the cell cycle is characterized as having a 1 mast cells (20), and thymocytes (22). A key experiment was to high rate of membrane phospholipid turnover. Increased incor- follow the pattern of phospholipid accumulation through the poration of label into phospholipids and elevated levels of in- second cell cycle following synchronization to convincingly dis- tracellular soluble phospholipid precursors were noted after tinguish that membrane phospholipid acquisition was a cell the mitogenic stimulation of cells (3, 4), although these studies cycle-regulated process rather than a growth factor-triggered did not address whether the increase in labeling represented event that took several hours to initiate (12). The distribution net phospholipid synthesis or enhanced phospholipid turnover of major phospholipid classes in whole cells was essentially (5–11). Jackowski (12) examined both synthesis and degrada- constant throughout the cell cycle in NIH fibroblasts (11). Like- tion in a macrophage cell line using a double label experiment wise, the content of PtdIns, PtdIns-P, and PtdIns-P was rela- and attributed the increase in choline incorporation into Ptd- tively constant during the cell cycle (23), although specific Cho during G (4) to rapid PtdCho turnover (12). Importantly, changes have been observed in the nuclear compartment (see below). Net phospholipid accumulation is coordinated with S phase * This minireview will be reprinted in the 1996 Minireview Compen- dium, which will be available in December, 1996. This work was sup- of the cell cycle, but phospholipid synthesis is not dependent on ported by United States Public Health Service Grant GM45737 from DNA synthesis. Cell cycle arrest of a macrophage cell line in NIGMS, Cancer Center (CORE) Support Grant CA21765, and the mid-G with dibutyryl-cAMP or at the G /S boundary with 1 1 American and Lebanese Syrian Associated Charities. aphidicolin prevented S phase DNA synthesis; however, net ‡ To whom correspondence should be addressed: Biochemistry Dept., St. Jude Children’s Research Hospital, 332 N. Lauderdale, Memphis, phospholipid accumulation continued (12). These data illus- TN 38101. trated that the decision to double the phospholipid mass was The abbreviations used are: PtdCho, phosphatidylcholine; PtdEtn, phosphatidylethanolamine; PtdIns, phosphatidylinositol; PtdIns-P, phosphatidylinositol 4-phosphate; PtdIns-P , phosphatidylinositol 4,5- bisphosphate; CT, CTP:phosphocholine cytidylyltransferase. This is an open access article under the CC BY license. 20219 20220 Minireview: Phospholipids and the Cell Cycle made in early G , or perhaps M phase of the previous cell cycle, nase C, which, in turn, has been found to phosphorylate and and proceeded concurrently, but independently, of DNA repli- activate DNA polymerase and topoisomerase (30, 38). York et cation. The nature of the signal that licenses the cell to double al. (39) demonstrated the existence of a nuclear inositol polyphosphate-1-phosphatase. The overexpression of this ino- its membrane phospholipid mass is unknown but is likely to involve the expression or modification of key regulators in early sitol polyphosphate-1-phosphatase inhibited DNA synthesis, thus providing compelling evidence for inositol polyphosphates G . The overall phospholipid composition of isolated nuclei is not as determinants in the control of DNA synthesis. One likely candidate for nuclear signaling is inositol 1,4-bisphosphate markedly different from the whole cell; PtdCho, PtdEtn, and since this compound could bind to DNA polymerase and en- sphingomyelin are the predominant phospholipid species, and hance the affinity of the enzyme for DNA template/primer (40). PtdIns and its phosphorylated derivatives are represented as Alternatively, the identification of an inositol 1,4,5-trisphos- minor components (see Ref. 24 and references therein). Inter- phate receptor in the inner nuclear membrane that mediated estingly, nuclear phospholipids appear to be distributed within calcium release into the cytoplasm (41) indicated that inositol the interphase nucleus in addition to their presence in the polyphosphates played a role in regulating nuclear calcium nuclear membrane. Amorphous lipoprotein complexes were concentration, which in turn could influence DNA replication identified morphologically in the interphase cell nucleus, local- and gene transcription (42). Establishing the critical nuclear ized mainly in the interchromatin spaces and in the nucleolar target(s) and determining their function in the initiation and domain. Furthermore, a decrease in the overall nuclear phos- control of S phase DNA replication will be an interesting pholipid content was associated with DNA replication (25); challenge. however, the morphological analysis did not reveal whether this decrease was due to the disappearance of a specific phos- G and M Phases pholipid class. The apparent co-localization of phospholipids Much less is known about phospholipid metabolism in G and ribonucleoproteins suggested a role for phospholipid in the and M phases. There was little overall phospholipid synthesis mechanism of transport and release of transcripts. For exam- or degradation occurring in these latter stages based on meta- ple, the release of ribonucleoproteins after phospholipase A bolic labeling of macrophage cells synchronized by growth fac- digestion of the nucleus indicated that phospholipids may me- tor withdrawal (12). The paucity of information is due in part to diate the binding between ribonucleoprotein and the nuclear the difficulty in analyzing pure populations of cells in these matrix (24). The importance of these morphological observa- phases of the cell cycle. The G and S phases are between 6 and tions to the biochemical events taking place in the nucleus is a 12 h in length making it relatively easy to isolate adequate challenging area for future research. numbers of cells. However, the G /M phases are considerably Nuclear inositol phospholipid metabolism is a significant S shorter (2–4 h), and synchronous cell populations in G /M are phase-specific event. The enzymes of polyphosphoinositide contaminated with cells in S and G phases. Nocodazole is an turnover occur in the nucleus (for review see Ref. 26), and there effective agent that arrests cells in M phase; however, the use is considerable evidence for PtdIns-P synthesis (27, 28) and of cell cycle blockers can be problematic without corroboration degradation in the nuclear matrix (29–31). Nuclear PtdIns, from experiments with synchronous or elutriated cells. PtdIns-P, and PtdIns-P decreased coincident with S phase in The most significant event involving phospholipids in M HeLa cells (23), and the levels of all of the inositol phosphates phase is the cessation of membrane trafficking concomitant increased at both the G /S boundary and in S phase in the with the destruction and reassembly of the nuclear membrane nucleus of synchronized neuroblastoma cells (32). These data (43). While the dynamic aspects of the assembly of nuclear suggested that the PtdIns cycle was activated in S phase nuclei membrane protein components have received considerable ex- and implied the presence of a nuclear PtdIns-P phospholipase perimental attention (44), the phospholipid components have C that was specifically regulated during S phase. Phospho- not been studied in detail. Metabolic labeling of Chinese ham- lipase Cb1 is present in the nuclei of Swiss 3T3 cells and was ster ovary cells indicated that at least 50% of the nuclear postulated to be involved in the rapid responses of quiescent envelope phospholipid present in G was used to resynthesize (G ) cells stimulated to enter G by insulin growth factor-1 (33). 0 1 the nuclear envelopes of the daughter cells (45). Studies with More recently, Asano et al. (34) purified a novel phospholipase Amoeba proteus are worthy of mention because of their unique C isozyme that was only detected in the nuclei of regenerating approach (46). Autoradiographic observations following im- rat liver. Subsequently, a new isoform of PtdIns-specific phos- plantation of [ H]choline-labeled nuclei into unlabeled cells pholipase C (Cd4) was cloned, purified, and characterized by revealed little turnover of nuclear membrane phospholipid dur- two laboratories (35, 36). Importantly, phospholipase Cd4 was ing interphase; however, during mitosis the label was dis- primarily present in the nucleus, dramatically increased at the persed throughout the cytoplasm coincident with the degrada- G /S transition, and virtually disappeared by the time cells tion of the nuclear envelope. The cytoplasmic label was re-entered the next G phase (36). Thus, phospholipase Cd4 has subsequently divided equally among the daughter cell nuclei. the biological properties anticipated for the enzyme that regu- These data indicated that the nuclear envelope was recon- lates nuclear phosphoinositide metabolism during S phase, and structed from pre-existing phospholipids as the cells exited M it will be important to determine if its activity is regulated by phase and entered early G . The role of phospholipid trafficking cell cycle-specific expression alone or whether there is an ad- in the dissolution and reformation of the nuclear envelope ditional level of activity regulation by cyclin-dependent protein promises to be an exciting area for future investigation. kinases. Biochemical Mechanisms The products of polyphosphoinositide breakdown are thought to play a role in DNA synthesis, consistent with their The search for the biochemical mechanism underlying the formation during S phase. Treatment of the nuclear matrix periodic accumulation of membrane phospholipid has focused with phospholipase C released nucleic acid suggesting that on the control of PtdCho synthesis and degradation. PtdCho is polyphosphoinositides mediated the association of DNA with not only the most abundant membrane phospholipid, but it is the matrix (37), an interaction that may have to be disrupted also serves as the precursor for the other two predominant for efficient DNA synthesis. Alternatively, the diacylglycerol phospholipid species, PtdEtn (47) and sphingomyelin (48). released by phospholipase C may activate nuclear protein ki- Most cells are capable of synthesizing PtdEtn via CTP:phos- Minireview: Phospholipids and the Cell Cycle 20221 phoethanolamine cytidylyltransferase and ethanolamine phos- photransferase; however, tissue culture media lack ethanola- mine. Therefore, the CDP-ethanolamine pathway cannot contribute to bulk membrane formation in tissue culture sys- tems although it is likely to be important in PtdEtn turnover (49). CT is a key regulatory enzyme in PtdCho biosynthesis and hence phospholipid formation (50). CT is extensively phospho- rylated on its carboxyl-terminal domain in vivo (51), and CT phosphorylation is associated with the inhibition of enzyme activity (12, 52). Importantly, the extent of CT phosphorylation fluctuates with the cell cycle, and maximum CT phosphoryla- tion occurs in the G /M phase and correlates with the cessation of phospholipid synthesis (12). Nuclear CT (53–56, 68) is in the correct subcellular compartment for regulation by cyclin-de- pendent kinases, and the observation that CT is phosphoryl- ated to some extent in vitro by Cyclin B/Cdc2 kinase (57, 69) suggests that the regulators of the cell cycle control the pace of FIG.1. Relationship between phospholipid metabolism and phospholipid synthesis through the direct phosphorylation of the cell cycle. G phase is characterized by a high rate of PtdCho degradation and resynthesis that is dependent on growth factor and CT. However, CT activity regulation by cyclin-dependent pro- terminates at the G /S boundary. Doubling of the phospholipid mass tein kinase phosphorylation has not been directly demon- occurs in S phase due to continued phospholipid synthesis but with strated, and there are likely to be additional enzymes (i.e. those drastically reduced phospholipid turnover. The turnover of nuclear responsible for PtdCho degradation) that contribute to the ob- polyphosphoinositides is an additional S phase event that may be a component of a regulatory network that governs DNA replication. The served periodicity in membrane formation. Identifying these G and M phases are characterized by the cessation of phospholipid enzymes and their modes of regulation is obviously important metabolism. to completing the understanding of cell cycle regulation of phospholipid metabolism. phospholipid accumulation and the inhibition of phospholipid Do Lipids Regulate the Cell Cycle? synthesis did not have an immediate impact on DNA replica- tion (63). S phase is also associated with the turnover of nuclear While it is apparent that the cell cycle controls bulk phos- pholipid and membrane biogenesis, it is not clear whether the polyphosphoinositides that generate messengers thought to be components of DNA replication. G and M phases are charac- cell cycle is in turn influenced by lipid content. Several studies reported that the inhibition of fatty acid and/or phospholipid terized by a cessation of phospholipid metabolism where both synthesis and degradation of membrane lipid components synthesis by nutritional deprivation (i.e. biotin or choline star- reach their nadir. This conceptual model serves as the spring- vation) led to the accumulation of several cell types in G board for launching future investigation into the underlying (58–61). When C3H/10T1/2 fibroblasts were deprived of cho- biochemical mechanisms. line and synchronized in G by incubation in low serum, the Virtually nothing is known about the key regulatory en- cells did not efficiently enter S phase following serum restimu- zymes or the biochemical mechanisms employed during the cell lation suggesting that PtdCho synthesis was a requirement for cycle to generate the periodic pattern of phospholipid metabo- S phase entry (61). However, cells deprived of choline contin- lism. Cell cycle regulation is governed by the activity of cyclin- ued to divide for several days (61), and Chinese hamster ovary dependent protein kinases (64–66); therefore, it seems likely cells with a temperature-sensitive defect in CT activity contin- that these kinases either directly or indirectly deliver regula- ued to grow for several doublings in the absence of PtdCho tory signals to key enzymes in phospholipid biosynthesis. One synthesis via the de novo pathway (62). These latter data of the most interesting remaining questions is how does the suggest that proliferating cells do not detect phospholipid con- phospholipid biosynthetic apparatus obtain a license to double tent as a determinant of cell cycle progression. However, ex- the membrane phospholipid mass? This permit is issued in amining the state of cyclins and their associated kinases in early G since blocking the cell cycle in either mid-G or at the cells arrested by choline starvation or in the temperature- 1 1 G /S boundary does not prevent doubling of the phospholipid sensitive CT mutants may reveal a relationship between phos- mass. Cyclin D-dependent protein kinases are the first cell pholipid metabolism and cell cycle control that is not apparent cycle-regulated kinases to appear in G (65) making them can- from these experiments. Alternatively, the accumulation of didate regulators of membrane phospholipid licensing. The ces- cells deficient in phospholipid in G may reflect a requirement sation of rapid PtdCho turnover at the G /S boundary contrib- for the high degradation or turnover of PtdCho that occurs utes to the accumulation of phospholipid in S phase. Cyclin during this phase of the cell cycle, which in turn demands an E/Cdk2 and Cyclin A/Cdk2 are two candidate cyclin-dependent accelerated rate of lipid synthesis. protein kinases that are expressed in late G and early S phase Concluding Remarks that may be regulators of PtdCho turnover by phosphorylating The experiments to date lead to a conceptual model for the and inhibiting the responsible enzyme(s). Alternatively, Ptd- modulation of phospholipid metabolism during the cell cycle Cho turnover may be positively regulated by growth factor (Fig. 1). The G phase is characterized by rapid synthesis and signaling. For example, colony-stimulating factor 1 was re- degradation of PtdCho that continues up to the G /S boundary. quired through most of G in order for macrophage cells to 1 1 PtdCho metabolism is so rapid that some cells turn over about enter S phase (67) and also stimulate PtdCho turnover (15). 75% of their total PtdCho during G . In S phase, PtdCho Therefore, the cessation of growth factor signaling in late G 1 1 turnover ceases, and the cells double their membrane phospho- may account for the concomitant cessation of PtdCho turnover. lipid content in preparation for cell division. Although DNA It will also be important to determine if nuclear phospholipase replication and expansion of the membrane phospholipid pool Cd4, polyphosphoinositol phosphatases, and PtdIns kinases are are coordinated with the cell cycle, they are not dependent on regulated by the cyclin-dependent protein kinases that are each other since inhibition of DNA replication did not block required for cells to initiate and traverse S phase. Finally, 20222 Minireview: Phospholipids and the Cell Cycle Biophys. Res. Commun. 218, 182–186 phospholipid synthesis reaches its nadir in the G and M 28. Cocco, L., Gilmour, R. S., Ognibene, A., Letcher, A. J., Manzoli, F. A., and phases, a stage characterized by the activation of Cyclin Irvine, R. F. 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