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From the Department of Biochemistry, St. Jude Children's Research
Hospital, Memphis, Tennessee 38101 and the University of Tennessee,
Memphis, Tennessee 38163
INTRODUCTION This review focuses on the phospholipid
metabolism regulated by the cell cycle. Phospholipids are the major
cellular constituents required for the assembly of biological
membranes, and cells must double their phospholipid mass to form
daughter cells. It seems reasonable that this event should coincide
with the synthesis of other cellular components such as DNA, stable
RNA, etc.; however, the biochemical mechanisms that coordinate
macromolecular and bulk membrane phospholipid production are largely
unknown. The importance of these regulatory processes to cell
physiology is obvious. Discordant regulation of phospholipid
accumulation by only a few percent per cell cycle would rapidly result
in cells with either a large excess or deficit of membrane surface
leading to abnormalities in cell size and/or intracellular lipid
accumulation. Thus, stringent control mechanisms must be in place to
keep the phospholipid content in tune with the cell cycle. This
discussion will explore the state of our knowledge in cultured
mammalian cell systems, although cell cycle-regulated phospholipid
accumulation occurs in lower eukaryotes such as Saccharomyces
cerevisiae (1) and Caulobacter crescentus (2). This
review is limited to a discussion of events that are directly tied to
the cell cycle. Phospholipid metabolism in response to mitogenic
stimulation will not be addressed as these biochemical events are
generally associated with the G0 to G1
transition and are ligand-regulated rather than being orchestrated by
the cell cycle.
G1 Phase The G1 phase of the cell cycle is characterized as
having a high rate of membrane phospholipid turnover. Increased
incorporation of label into phospholipids and elevated levels of
intracellular soluble phospholipid precursors were noted after the
mitogenic stimulation of cells (3, 4), although these studies did not
address whether the increase in labeling represented net phospholipid
synthesis or enhanced phospholipid turnover (5, 6, 7, 8, 9, 10, 11). Jackowski (12)
examined both synthesis and degradation in a macrophage cell line using
a double label experiment and attributed the increase in choline
incorporation into PtdCho1 during
G1 (4) to rapid PtdCho turnover (12). Importantly, the rate
of PtdCho degradation decreased by an order of magnitude in S phase and
then accelerated again as the cells entered the next G1
period, thereby establishing that PtdCho turnover in G1 was
associated with the cell cycle and not a property of the G0
to G1 transition (12). The cessation of PtdCho degradation
in S phase is likely an important contributor to the net accumulation
of phospholipid during this time; however, nothing is known about the
biochemical processes that govern the periodicity of PtdCho
turnover.
PtdCho turnover may be an important aspect of phospholipid metabolism
during G1 that is necessary, and in some cases, sufficient
for entry into S phase. PtdCho hydrolysis by phospholipase C and/or D
pathways is triggered by a wide array of agonists (9), and both
exogenous bacterial PtdCho phospholipase C (13) and PtdCho
phospholipase D (14) added to the medium mimicked the mitogenic effect
of platelet-derived growth factor. The fact that PtdCho phospholipase
C, like growth factors, was required throughout G1 for
maximal mitogenic effect (15) supports a causal relationship between
PtdCho turnover and G1 progression. The precise signal
transduction pathways activated by PtdCho phospholipase C remain to be
clarified, although activation of the Ras-Raf pathway (16, 17) and/or
protein kinase C S Phase The net accumulation of phospholipid is a periodic event
associated with S phase of the cell cycle. The first experiments
established that phospholipid synthesis occurred during interphase as
opposed to mitosis (19, 20). Subsequent measurements of the amount of
phospholipid per cell during the first 12 h after mitogenic
stimulation revealed little increase, whereas there was a significant
rise in cellular phospholipid content between 12 and 24 h (21,
22). In these studies, the first 12 h corresponded to the exit
from G0 together with the G1 phase of the cell
cycle, whereas the time between 12 and 24 h corresponded to S,
G2, and M phases. A more detailed analysis revealed that
phospholipid content doubled specifically during S phase (12, 20). This
pattern of net phospholipid accumulation was consistent among a number
of mammalian cell types including fibroblasts (21), HeLa cells (19),
macrophages (12), mast cells (20), and thymocytes (22). A key
experiment was to follow the pattern of phospholipid accumulation
through the second cell cycle following synchronization to convincingly
distinguish that membrane phospholipid acquisition was a cell
cycle-regulated process rather than a growth factor-triggered event
that took several hours to initiate (12). The distribution of major
phospholipid classes in whole cells was essentially constant throughout
the cell cycle in NIH fibroblasts (11). Likewise, the content of
PtdIns, PtdIns-P, and PtdIns-P2 was relatively constant
during the cell cycle (23), although specific changes have been
observed in the nuclear compartment (see below).
Net phospholipid accumulation is coordinated with S phase of the cell
cycle, but phospholipid synthesis is not dependent on DNA synthesis.
Cell cycle arrest of a macrophage cell line in mid-G1 with
dibutyryl-cAMP or at the G1/S boundary with aphidicolin
prevented S phase DNA synthesis; however, net phospholipid accumulation
continued (12). These data illustrated that the decision to double the
phospholipid mass was made in early G1, or perhaps M phase
of the previous cell cycle, and proceeded concurrently, but
independently, of DNA replication. The nature of the signal that
licenses the cell to double its membrane phospholipid mass is unknown
but is likely to involve the expression or modification of key
regulators in early G1.
The overall phospholipid composition of isolated nuclei is not markedly
different from the whole cell; PtdCho, PtdEtn, and sphingomyelin are
the predominant phospholipid species, and PtdIns and its phosphorylated
derivatives are represented as minor components (see Ref. 24 and
references therein). Interestingly, nuclear phospholipids appear to be
distributed within the interphase nucleus in addition to their presence
in the nuclear membrane. Amorphous lipoprotein complexes were
identified morphologically in the interphase cell nucleus, localized
mainly in the interchromatin spaces and in the nucleolar domain.
Furthermore, a decrease in the overall nuclear phospholipid content was
associated with DNA replication (25); however, the morphological
analysis did not reveal whether this decrease was due to the
disappearance of a specific phospholipid class. The apparent
co-localization of phospholipids and ribonucleoproteins suggested a
role for phospholipid in the mechanism of transport and release of
transcripts. For example, the release of ribonucleoproteins after
phospholipase A2 digestion of the nucleus indicated that
phospholipids may mediate the binding between ribonucleoprotein and the
nuclear matrix (24). The importance of these morphological observations
to the biochemical events taking place in the nucleus is a challenging
area for future research.
Nuclear inositol phospholipid metabolism is a significant S
phase-specific event. The enzymes of polyphosphoinositide turnover
occur in the nucleus (for review see Ref. 26), and there is
considerable evidence for PtdIns-P2 synthesis (27, 28) and
degradation in the nuclear matrix (29, 30, 31). Nuclear PtdIns, PtdIns-P,
and PtdIns-P2 decreased coincident with S phase in HeLa
cells (23), and the levels of all of the inositol phosphates increased
at both the G1/S boundary and in S phase in the nucleus of
synchronized neuroblastoma cells (32). These data suggested that the
PtdIns cycle was activated in S phase nuclei and implied the presence
of a nuclear PtdIns-P2 phospholipase C that was
specifically regulated during S phase. Phospholipase C The products of polyphosphoinositide breakdown are thought to play a
role in DNA synthesis, consistent with their formation during S phase.
Treatment of the nuclear matrix with phospholipase C released nucleic
acid suggesting that polyphosphoinositides mediated the association of
DNA with the matrix (37), an interaction that may have to be disrupted
for efficient DNA synthesis. Alternatively, the diacylglycerol released
by phospholipase C may activate nuclear protein kinase C, which, in
turn, has been found to phosphorylate and activate DNA polymerase and
topoisomerase (30, 38). York et al. (39) demonstrated the
existence of a nuclear inositol polyphosphate-1-phosphatase. The
overexpression of this inositol polyphosphate-1-phosphatase inhibited
DNA synthesis, thus providing compelling evidence for inositol
polyphosphates as determinants in the control of DNA synthesis. One
likely candidate for nuclear signaling is inositol 1,4-bisphosphate
since this compound could bind to DNA polymerase and enhance the
affinity of the enzyme for DNA template/primer (40). Alternatively, the
identification of an inositol 1,4,5-trisphosphate receptor in the inner
nuclear membrane that mediated calcium release into the cytoplasm (41)
indicated that inositol polyphosphates played a role in regulating
nuclear calcium concentration, which in turn could influence DNA
replication and gene transcription (42). Establishing the critical
nuclear target(s) and determining their function in the initiation and
control of S phase DNA replication will be an interesting
challenge.
G2 and M Phases Much less is known about phospholipid metabolism in G2
and M phases. There was little overall phospholipid synthesis or
degradation occurring in these latter stages based on metabolic
labeling of macrophage cells synchronized by growth factor withdrawal
(12). The paucity of information is due in part to the difficulty in
analyzing pure populations of cells in these phases of the cell cycle.
The G1 and S phases are between 6 and 12 h in length
making it relatively easy to isolate adequate numbers of cells.
However, the G2/M phases are considerably shorter (2-4 h),
and synchronous cell populations in G2/M are contaminated
with cells in S and G1 phases. Nocodazole is an effective
agent that arrests cells in M phase; however, the use of cell cycle
blockers can be problematic without corroboration from experiments with
synchronous or elutriated cells.
The most significant event involving phospholipids in M phase is the
cessation of membrane trafficking concomitant with the destruction and
reassembly of the nuclear membrane (43). While the dynamic aspects of
the assembly of nuclear membrane protein components have received
considerable experimental attention (44), the phospholipid components
have not been studied in detail. Metabolic labeling of Chinese hamster
ovary cells indicated that at least 50% of the nuclear envelope
phospholipid present in G2 was used to resynthesize the
nuclear envelopes of the daughter cells (45). Studies with Amoeba
proteus are worthy of mention because of their unique approach
(46). Autoradiographic observations following implantation of
[3H]choline-labeled nuclei into unlabeled cells revealed
little turnover of nuclear membrane phospholipid during interphase;
however, during mitosis the label was dispersed throughout the
cytoplasm coincident with the degradation of the nuclear envelope. The
cytoplasmic label was subsequently divided equally among the daughter
cell nuclei. These data indicated that the nuclear envelope was
reconstructed from pre-existing phospholipids as the cells exited M
phase and entered early G1. The role of phospholipid
trafficking in the dissolution and reformation of the nuclear envelope
promises to be an exciting area for future investigation.
Biochemical Mechanisms The search for the biochemical mechanism underlying the periodic
accumulation of membrane phospholipid has focused on the control of
PtdCho synthesis and degradation. PtdCho is not only the most abundant
membrane phospholipid, but it is also serves as the precursor for the
other two predominant phospholipid species, PtdEtn (47) and
sphingomyelin (48). Most cells are capable of synthesizing PtdEtn via
CTP:phosphoethanolamine cytidylyltransferase and ethanolamine
phosphotransferase; however, tissue culture media lack ethanolamine.
Therefore, the CDP-ethanolamine pathway cannot contribute to bulk
membrane formation in tissue culture systems 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 phosphorylated 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
phosphorylation occurs in the G2/M phase and correlates
with the cessation of phospholipid synthesis (12). Nuclear CT (53, 54, 55, 56,
68) is in the correct subcellular compartment for regulation by
cyclin-dependent kinases, and the observation that CT is
phosphorylated to some extent in vitro by Cyclin B/Cdc2
kinase (57, 69) suggests that the regulators of the cell cycle control
the pace of phospholipid synthesis through the direct phosphorylation
of CT. However, CT activity regulation by cyclin-dependent
protein kinase phosphorylation has not been directly demonstrated, and
there are likely to be additional enzymes (i.e. those
responsible for PtdCho degradation) that contribute to the observed
periodicity in membrane formation. Identifying these enzymes and their
modes of regulation is obviously important to completing the
understanding of cell cycle regulation of phospholipid metabolism.
Do Lipids Regulate the Cell Cycle? While it is apparent that the cell cycle controls bulk
phospholipid and membrane biogenesis, it is not clear whether the cell
cycle is in turn influenced by lipid content. Several studies reported
that the inhibition of fatty acid and/or phospholipid synthesis by
nutritional deprivation (i.e. biotin or choline starvation)
led to the accumulation of several cell types in G1
(58, 59, 60, 61). When C3H/10T1/2 fibroblasts were deprived of choline and
synchronized in G1 by incubation in low serum, the cells
did not efficiently enter S phase following serum restimulation
suggesting that PtdCho synthesis was a requirement for S phase entry
(61). However, cells deprived of choline continued to divide for
several days (61), and Chinese hamster ovary cells with a
temperature-sensitive defect in CT activity continued to grow for
several doublings in the absence of PtdCho synthesis via the de
novo pathway (62). These latter data suggest that proliferating
cells do not detect phospholipid content as a determinant of cell cycle
progression. However, examining the state of cyclins and their
associated kinases in cells arrested by choline starvation or in the
temperature-sensitive CT mutants may reveal a relationship between
phospholipid metabolism and cell cycle control that is not apparent
from these experiments. Alternatively, the accumulation of cells
deficient in phospholipid in G1 may reflect a requirement
for the high degradation or turnover of PtdCho that occurs during this
phase of the cell cycle, which in turn demands an accelerated rate of
lipid synthesis.
Concluding Remarks The experiments to date lead to a conceptual model for the
modulation of phospholipid metabolism during the cell cycle (Fig.
1). The G1 phase is characterized by rapid
synthesis and degradation of PtdCho that continues up to the
G1/S boundary. PtdCho metabolism is so rapid that some
cells turn over about 75% of their total PtdCho during G1.
In S phase, PtdCho turnover ceases, and the cells double their membrane
phospholipid content in preparation for cell division. Although DNA
replication and expansion of the membrane phospholipid pool are
coordinated with the cell cycle, they are not dependent on each other
since inhibition of DNA replication did not block phospholipid
accumulation and the inhibition of phospholipid synthesis did not have
an immediate impact on DNA replication (63). S phase is also associated
with the turnover of nuclear polyphosphoinositides that generate
messengers thought to be components of DNA replication. G2
and M phases are characterized by a cessation of phospholipid
metabolism where both synthesis and degradation of membrane lipid
components reach their nadir. This conceptual model serves as the
springboard for launching future investigation into the underlying
biochemical mechanisms.
Virtually nothing is known about the key regulatory enzymes or the
biochemical mechanisms employed during the cell cycle to generate the
periodic pattern of phospholipid metabolism. Cell cycle regulation is
governed by the activity of cyclin-dependent protein
kinases (64, 65, 66); therefore, it seems likely that these kinases either
directly or indirectly deliver regulatory signals to key enzymes in
phospholipid biosynthesis. One of the most interesting remaining
questions is how does the phospholipid biosynthetic apparatus obtain a
license to double the membrane phospholipid mass? This permit is issued
in early G1 since blocking the cell cycle in either
mid-G1 or at the G1/S boundary does not prevent
doubling of the phospholipid mass. Cyclin D-dependent
protein kinases are the first cell cycle-regulated kinases to appear in
G1 (65) making them candidate regulators of membrane
phospholipid licensing. The cessation of rapid PtdCho turnover at the
G1/S boundary contributes to the accumulation of
phospholipid in S phase. Cyclin E/Cdk2 and Cyclin A/Cdk2 are two
candidate cyclin-dependent protein kinases that are
expressed in late G1 and early S phase that may be
regulators of PtdCho turnover by phosphorylating and inhibiting the
responsible enzyme(s). Alternatively, PtdCho turnover may be positively
regulated by growth factor signaling. For example, colony-stimulating
factor 1 was required through most of G1 in order for
macrophage cells to enter S phase (67) and also stimulate PtdCho
turnover (15). Therefore, the cessation of growth factor signaling in
late G1 may account for the concomitant cessation of PtdCho
turnover. It will also be important to determine if nuclear
phospholipase C FOOTNOTES REFERENCES
Volume 271, Number 34,
Issue of August 23, 1996
pp. 20219-20222
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.
MINIREVIEW:
INTRODUCTION
G1 Phase
S Phase
G2 and M Phases
Biochemical Mechanisms
Do Lipids Regulate the Cell Cycle?
Concluding Remarks
FOOTNOTES
REFERENCES
(18) may be involved.
1 is present
in the nuclei of Swiss 3T3 cells and was postulated to be involved in
the rapid responses of quiescent (G0) cells stimulated to
enter G1 by insulin growth factor-1 (33). More recently,
Asano et al. (34) purified a novel phospholipase C isozyme
that was only detected in the nuclei of regenerating rat liver.
Subsequently, a new isoform of PtdIns-specific phospholipase C (C
4)
was cloned, purified, and characterized by two laboratories (35, 36).
Importantly, phospholipase C4 was primarily present in the nucleus,
dramatically increased at the G1/S transition, and
virtually disappeared by the time cells re-entered the next
G1 phase (36). Thus, phospholipase C4 has the biological
properties anticipated for the enzyme that regulates nuclear
phosphoinositide metabolism during S phase, and it will be important to
determine if its activity is regulated by cell cycle-specific
expression alone or whether there is an additional level of activity
regulation by cyclin-dependent protein kinases.
Fig. 1.
Relationship between phospholipid metabolism
and the cell cycle. G1 phase is characterized by a
high rate of PtdCho degradation and resynthesis that is dependent on
growth factor and terminates at the G1/S boundary. Doubling
of the phospholipid mass occurs in S phase due to continued
phospholipid synthesis but with drastically reduced phospholipid
turnover. The turnover of nuclear polyphosphoinositides is an
additional S phase event that may be a component of a regulatory
network that governs DNA replication. The G2 and M phases
are characterized by the cessation of phospholipid metabolism.
4, polyphosphoinositol phosphatases, and PtdIns
kinases are regulated by the cyclin-dependent protein
kinases that are required for cells to initiate and traverse S phase.
Finally, phospholipid synthesis reaches its nadir in the G2
and M phases, a stage characterized by the activation of Cyclin B/Cdc2
kinase. CT is currently the only candidate for a key regulator of cell
cycle-dependent membrane phospholipid biosynthesis;
however, other candidate regulators are likely to arise from the
ongoing investigation of the biochemical mechanisms responsible for
coordinating membrane formation with cell division. The role of
phospholipid trafficking in the dissolution and reformation of the
nuclear envelope is also a fertile area for investigation. The
solutions to these questions present major experimental challenges, but
the answers promise exciting new insights into the biochemical
processes that govern membrane formation and cell division.
To whom correspondence should be addressed: Biochemistry Dept.,
St. Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, TN
38101.
1
The abbreviations used are: PtdCho,
phosphatidylcholine; PtdEtn, phosphatidylethanolamine; PtdIns,
phosphatidylinositol; PtdIns-P, phosphatidylinositol 4-phosphate;
PtdIns-P2, phosphatidylinositol 4,5-bisphosphate; CT,
CTP:phosphocholine cytidylyltransferase.
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.
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