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2
Early Embryonic Cell Cycle
Many biological processes are best studied in cells
that are specialized for particular tasks.
For
example, studies on nerve cells have been the
principal route to understanding the electrical
properties of cells, and studies on muscle provided
the foundation of our knowledge about how chemical
energy is converted into movement.
Because eggs are
specialized for rapid cell division, it is not
surprising that studies of them have made a
fundamental contribution to unraveling the mysteries
of the cell cycle.
Nineteenth-century biologists first appreciated the
advantages of eggs for studying the cell cycle, and
they meticulously observed and beautifully described
the early embryonic cell cycles of marine invertebrate
and amphibian eggs.
They recognized the division of
the cell cycle into interphase and mitosis, and their
observations on mitosis were remarkably accurate
(Figure 2-1).
But because at that time there was no
way to appreciate (much less understand) the
biochemical events that occurred in interphase, their
discussions concentrated on the mechanics of mitosis
and rarely speculated on the cell cycle as a whole.
In the first half of the twentieth century, interest
in eggs as experimental systems gradually declined,
reflecting the inability to extend observations from
microscopy to biochemistry.
During the 1960s,
however, progress in biochemical analysis and
reproductive physiology, together with the invention
of techniques to inject materials into living cells,
led to a resurgence in the use of eggs for studying
the cell cycle.
Since then, experiments on eggs have
contributed enormously to our knowledge of the cell
cycle.
Initially the techniques for injecting
materials were useful only with very large cells,
making frog eggs excellent subjects for analyzing the
early embryonic cell cycle.
The most widely used
source of eggs is the South African clawed frog,
Xenopus laevis.
This chapter describes studies on
frog eggs that identified the major inducer of mitosis
and led to the idea that a simple biochemical
oscillator drives the cell cycle.
EMBRYONIC CELL CYCLES
The eggs of amphibians, marine invertebrates, and
insects are large cells that can divide very rapidly.
A female frog can produce several thousand eggs, each
1 mm in diameter, that can be fertilized in vitro to
produce a large population of cells that proceed
synchronously through several cell cycles. The first
cell cycle lasts 75 minutes and is followed by 11
synchronous cell cycles, each 30 minutes long (Figure
2-2).
These divisions convert the originally solid
egg into a hollow ball of cells, called the blastula,
which then undergoes complex changes in shape that
produce a recognizable embryo (Figure 2-3).
In early
embryonic cell cycles, G1 and G2 are largely
suppressed, and the cycle consists essentially of a
regular alternation of extremely
rapid DNA replication and mitosis (see Figure 2-1).
After the twelfth mitosis the cell cycle slows, and
the synchrony between neighboring cells breaks down.
In this book "cell cycle:early embryonic" refers only
to these early, rapid, synchronous cell cycles.
cell cycle:early embryonic
The ability of eggs to divide without growing explains
why early embryonic cell cycles are faster than
somatic cell cycles.
Somatic cells are born small and
must import nutrients so that they can grow and
duplicate all the components of the cell.
Eggs,
however, are large and inherit from their mothers a
stock of nutrients, all the structural components of
the cell, and almost all the enzymes that catalyze the
processes of the cell cycle.
As a result, apart from
replicating their DNA, early embryonic cells have to
produce only a handful of new components to proceed
through a cell cycle that has been stripped to its
bare essentials.
Progesterone induces frog oocytes to enter meiosis and
become unfertilized eggs
The cells that give rise to eggs are called oocytes
and begin life at the same size as typical somatic
cells.
Shortly after birth, oocytes replicate their
DNA and then arrest in G2 for about 8 months as the
cells grow to a diameter of 1 mm
and stockpile the materials needed for the early
embryonic cell cycles.
To give rise to an egg, the
fully grown oocyte must halve its chromosome number to
convert itself from a diploid to a haploid cell so
that fusion with a haploid sperm will produce a
diploid embryo.
The oocyte produces a haploid egg by
going through the meiotic cell cycle, in which two
rounds of chromosome segregation follow a single round
of DNA replication .
When female frogs are appropriately stimulated, the
small cells that surround the oocyte secrete
progesterone.
This hormone acts on the oocyte,
leading to nuclear envelope breakdown, chromosome
condensation, and the assembly of the meiosis I
spindle (Figure 2-4).
The process takes about 5
hours, culminating in chromosome segregation and a
highly asymmetrical cell division that expels half the
chromosomes into a small cell known as the first polar
body. The oocyte immediately enters meiosis II but
arrests in metaphase for several hours as it travels
through the oviduct of the frog to emerge as an
unfertilized egg.
Fertilization releases eggs from
their metaphase arrest, allowing them to pass through
anaphase of meiosis II, produce a second polar body
and enter interphase of the first mitotic cell cycle.
The events that convert fully grown oocytes into
unfertilized eggs are known as meiotic maturation and
can be studied in vitro by adding progesterone to
oocytes that have been surgically removed from female
frogs.
Although several important differences exist
between the meiotic and mitotic cell cycles (see
Chapter 10), studies on the meiotic cell cycle were
what first identified the key factor that controls
both the meiotic and mitotic cell cycles.
Cytoplasmic transfer experiments reveal a maturation
promoting factor (MPF) that induces meiosis
The mammalian cell fusion experiments described in
Chapter 1 showed that mitosis dominates other states
in the cell cycle.
A similar result was obtained in
frog experiments, in which the transfer of cytoplasm
from eggs to oocytes demonstrated that meiosis is
dominant to interphase.
Isolated oocytes were treated
with progesterone to induce them to mature into
unfertilized eggs.
remove about 5%
A hollow microneedle was used to
of the cytoplasm from an egg and
inject it into an oocyte.
The recipient oocyte
matured as if it had been treated with progesterone
(Figure 2-5).
The injected oocytes that had matured
were then used as cytoplasmic donors to inject fresh
oocytes.
This second round of recipients also
matured, and they could in turn act as donors of
cytoplasm that induced yet another round of recipient
oocytes to mature.
The ability to perform many such
successive transfers showed that whatever promotes
maturation is a component of the unfertilized egg,
rather than progesterone carried over from the initial
hormonally matured oocyte.
For obvious reasons, the
activity that induces maturation was called Maturation
Promoting Factor (MPF).
MPF can also stand for
mitosis and meiosis promoting factor, a name that more
generally describes its role in the cell cycle.
Progesterone induces MPF activation and nuclear
envelope breakdown only if the treated oocytes are
allowed to synthesize proteins.
containing cytoplasm, however,
Injecting MPFinduces maturation
even if protein synthesis in the recipient oocyte is
inhibited.
This observation implies that oocytes must
contain molecules, called pre-MPF, that can be
converted into active MPF by a series of posttranslational reactions.
MPF activation is a purely cytoplasmic process, since
oocytes whose nuclei have been removed still produce
active MPF when treated with progesterone.
Thus, even
though MPF regulates the fate of the nucleus, the
nucleus is not required for the activation of MPF.
Progesterone
In fertilized eggs the activation of MPF requires
protein synthesis and induces entry into mitosis
How widespread is the role of MPF in the cell cycle?
The observation that oocytes could be induced to
mature by injecting cytoplasm from mitotically
arrested mammalian cells suggested that MPF exists in
a wide range of cell types.
The discovery that MPF
activity rises and falls in the meiotic and mitotic
cell cycles of frog eggs strengthened the suggestion
that MPF plays a key role in regulating the cell cycle
(Figure 2-6).
After treating oocytes with
progesterone, a 5 hour lag occurs before MPF activity
rises rapidly to a peak at metaphase of meiosis I.
Activity falls between the two meiotic divisions,
rises again as the meiosis II spindle is assembled and
then remains high during the natural cell cycle arrest
in metaphase of meiosis II.
Fertilization leads
rapidly to inactivation of MPF and interphase of the
first mitotic cell cycle.
After fertilization, MPF
activity rises each time the embryo enters mitosis and
then falls as it enters the next interphase.
In early embryonic cell cycles, entry into mitosis and
activation of MPF both require protein synthesis in
the preceding interphase.
The role of MPF in inducing
mitosis was investigated by injecting it into embryos
that had been arrested in interphase by treatment with
protein-synthesis inhibitors.
The injected embryos
entered mitosis, suggesting that the role of protein
synthesis in early embryonic cell cycles is limited to
inducing the activation of MPF (Figure 2-7).
The
presence of maternal stockpiles allows eggs to reduce
the role of protein synthesis to controlling of the
activities that regulate passage through the cell
cycle, unlike somatic cells which must synthesize more
of each component in each cell cycle.
Cytoplasmic transfer experiments
CELL CYCLE ENGINE
In most cells, inhibitors of DNA synthesis prevent
cells from entering mitosis, and inhibitors of spindle
assembly keep them from beginning anaphase, suggesting
that the completion of key steps in the replication
and segregation of the chromosomes could regulate MPF
activity.
Surprisingly, experiments on frog eggs led
to a very different conclusion.
The cell cycle engine in frog eggs oscillates
independently of DNA replication and spindle assembly
When fertilized frog eggs were treated with drugs that
inhibit DNA synthesis, the regular rise and fall of
MPF activity continued unabated (Figure 2-8).
As MPF
activity increased, the nuclei broke down, and as it
decreased, the nuclei re-formed, even though DNA
replication was completely blocked.
Treatment with
drugs that inhibit spindle assembly also failed to
prevent the regular oscillation of MPF activity or the
response of the nuclei to its rise and fall.
enucleated eggs MPF rose and fell normally.
Even in
Together
these experiments show that, in frog embryos, purely
cytoplasmic reactions activate and inactivate MPF and
drive the nucleus, whether ready or not, into and out
of mitosis.
This conclusion clearly violated the
dogma, derived from studies on somatic cells that the
progress of the cell cycle was regulated by the state
of the nucleus.
The experiments on the early embryonic frog cell cycle
suggested that it is controlled by a simple
biochemical oscillator that periodically drives cells
into and out of mitosis.
We now know that the
oscillator is a series of biochemical reactions in the
cytoplasm that collectively lead to the periodic
activation and inactivation of MPF.
When MPF activity
increases, the nuclei respond by breaking down and
forming a mitotic spindle.
When MPF activity
declines, anaphase and cytokinesis follow, and the
nucleus reassembles and replicates its DNA. In the
early frog embryo, changes in the activity of MPF
enforce changes in the state of the nucleus, but
events in the nucleus do not influence the activation
or inactivation of MPF.
Although the independence of the frog egg MPF cycle
from the nuclear cycle is unusual, even among
embryonic cell cycles, it helps classify events in the
cell cycle into two categories: reactions that make up
a cell cycle engine and downstream events that the
engine controls (Figure 2-9).
The cell cycle engine
consists of all the biochemical components, and the
reactions between them, that cause the periodic
activation and inactivation of MPF.
part of the engine.
MPF itself is
A major goal of cell cycle
research is to enumerate the components of the engine,
purify them, and use them to rebuild a working engine
in a test tube.
Downstream events lie outside the cell cycle engine
and are induced either by active MPF or by the
inactivation of MPF.
Active MPF induces the
downstream events of mitosis, including chromosome
condensation, nuclear envelope breakdown, and spindle
formation.
The inactivation of MPF induces the
downstream events that mark the exit from mitosis and
the beginning of interphase, including chromosome
segregation, chromosome decondensation, nuclear reformation, and cytokinesis.
In early embryonic cell
cycles, DNA replication and duplication of the
microtubule organizing center are also downstream
events induced by the inactivation of MPF.
In somatic
cell cycles, however, these processes are caused not
by the inactivation of MPF, but by an additional cell
cycle transition, called Start, that occurs during G1,
well after the inactivation of MPF (see Chapter 3).
Transitions in the cell cycle engine activate and
inactivate MPF
Dividing the processes of the cell cycle into a cell
cycle engine and a set of downstream events helps to
reveal the logic of the cell cycle.
The early
embryonic cell cycle engine has two states: mitosis,
where MPF is active, and interphase, where it is
inactive.
Transitions between these states induce the
downstream events that produce profound rearrangements
of the cell.
After each rearrangement is complete,
the architecture of the cell remains unchanged until
the next transition in the engine occurs (Figure 210).
Active MPF induces the changes that culminate in
metaphase, and the cell does not enter anaphase and
progress into interphase until the transition that
inactivates MPF.
Thus, the visible events of the cell
cycle reveal transitions in the state of the cell
cycle engine.
The main reason that we consider the
onset of anaphase marks the end of mitosis is that it
occurs very shortly after the inactivation of MPF, so
the end of mitosis directly reflects a change in the
state of the cell cycle engine.
The cell cycle engine is controlled more or less
tightly controlled in different cells.
In
unfertilized frog eggs the cell cycle engine is
arrested with high levels of MPF.
Fertilization
restarts the engine, which then runs freely, whether
or not downstream events are completed successfully.
In many embryos and all somatic cell cycles, each
transition in the engine is regulated in response to
the completion of downstream events.
.i).cell cycle:downstream events;
.ib.Cyclin:discovery;
The destruction of cyclins at the end of each mitosis
suggests a model for the cell cycle
What makes the cell cycle engine oscillate?
The
experiments on frog eggs suggested that the regular
oscillations in MPF activity drive the cell cycle but
did not reveal the molecular nature of MPF or the
enzymes that turn it on and off.
The only clue was
that protein synthesis was required to activate MPF in
every cell cycle.
were components,
Perhaps the newly made proteins
or activators, of MPF.
With the
benefit of hindsight, it now seems obvious that in
either case the critical proteins would have to be
used up or destroyed by passage through mitosis.
If
this were not true, it would be hard to explain why
new protein synthesis was required to activate MPF.
Many unsuccessful attempts were made to identify
periodic proteins, whose periodic synthesis had been
proposed to induce cell cycle transitions.
Then, as
often happens, what had been sought diligently,
was
stumbled upon accidentally.
The breakthrough came from studies of protein
synthesis in sea urchin eggs.
Newly fertilized eggs
were incubated with a radioactive amino acid and
sampled every 10 minutes to analyze the pattern of
radioactively labeled proteins.
The amount of
radioactivity in most proteins increased continuously
throughout the experiment, but one protein behaved
quite differently.
It disappeared abruptly at the end
of each mitosis and then gradually reappeared during
the next interphase (Figure 2-11).
Additional
experiments showed that cyclin, as it is now called,
is a periodic protein synthesized throughout the cell
cycle but degraded at the end of each mitosis.
The
assumption that periodic proteins are periodically
synthesized, rather than continuously synthesized and
periodically destroyed, may explain why cyclin
remained unidentified for so long.
The behavior of cyclin suggested a simple model of the
cell cycle engine, in which the activation of MPF
drives cells into mitosis and the decline of MPF
activity leads to the next interphase.
rests on three postulates:
The model
the accumulation of cyclin
during interphase activates MPF, active MPF induces
the destruction of cyclin, and the destruction of
cyclin leads to the inactivation of MPF.
In this
model the cell cycle engine flip-flops periodically
between mitosis and interphase (Figure 2-12).
The
accumulation of cyclin in interphase leads to the
activation of MPF and the induction of mitosis, and
the ability of MPF to induce the degradation of cyclin
leads to the inactivation of MPF and the next
interphase.
The model made three simple, testable
predictions: Cy-
clin is a protein that activates MPF or is a part of
MPF, cells must accumulate cyclin to enter mitosis,
and cells must degrade cyclin to exit mitosis.
Chapter 4 describes experiments that confirmed these
predictions and led ultimately to a more complex but
more realistic picture of the cell cycle engine.
Cyclins are found in all eukaryotes that have been
examined, including yeasts, coelenterates, flies,
echinoderms, mollusks, amphibians, mammals, and
plants.
We now know that there are many different
cyclins, which form a large family of related proteins
with different functions.
Mitotic cyclins (cyclin B)
are components of MPF, S phase cyclins (cyclin A) play
a poorly defined role in the control of DNA
replication, and G1 cyclins
are important in
catalyzing the events that move the somatic cell cycle
from G1 into S phase.
CONCLUSION
The experiments on MPF in frog eggs and oocytes and
the mammalian cell fusion experiments (see Chapter 1)
both led to the conclusion that mitotic cells contain
a dominant inducer of mitosis.
In other respects,
however, the two sets of experiments led to strikingly
different conclusions.
The studies of frog eggs
revealed a cytoplasmic oscillator that drives the
nucleus into
mitosis even if DNA replication is
unfinished, whereas in the fusion experiments cells
entered mitosis only after DNA synthesis was finished.
For many years the puzzling contrast between the
dictatorship of the cell cycle oscillator in frog eggs
and the interdependence of processes in the somatic
cell cycle suggested that the early embryonic and
somatic cycles were fundamentally different from each
other.
The ability to assay material for MPF activity meant
that oocyte injection offered a method for
characterizing and purifying MPF that the cell fusion
experiments did not offer.
hindered research on MPF.
Nevertheless, two problems
The first was purely
practical: MPF proved extraordinarily difficult to
characterize and purify, partly because the oocyte
injection assay was cumbersome and technically
demanding.
Second, the possibility that MPF is active
only in the specialized meiotic cell cycle meant that
few people studied it until the evidence for its role
in the mitotic cell cycle was overwhelming.
As we
shall see in Chapter 4, the pace of research on MPF
increased exponentially during the 1980s, leading to
the discovery that it is a universal component of a
highly conserved cell cycle engine found in all
eukaryotes.
SELECTED READINGS
General
Wilson, E.B. The cell in development and heredity, 3rd
ed.
1232 pp. (Macmillan, New York, 1928).
This
classical summary of the work of early light
microscopists reveals the strengths and weaknesses of
a purely descriptive approach to the cell cycle.
Original articles
Masui, Y., & Markert, C.L.
Cytoplasmic
control of
nuclear behavior during meiotic maturation of frog
oocytes.
J .Exp .Zool . 177, 129-145 (1971).
The
discovery of MPF.
Gerhart, J., Wu, M., & Kirschner, M.
Cell cycle
dynamics of an M-phase-specific cytoplasmic factor in
Xenopus laevis oocytes and eggs.
1247-1255 (1984).
J. Cell Biol. 98,
Inhibitors of spindle assembly fail
to prevent the regular oscillation of MPF activity.
Newport, J.W., & Kirschner, M.W.
Regulation of the
cell cycle during early Xenopus development.
37, 731-742 (1984).
Cell
Injection of MPF into interphase cells induces them to
enter mitosis.
Evans, T., Rosenthal, E.T., Youngblom, J., Distel, D.,
& Hunt, T.
Cyclin:
A protein specified
by maternal
mRNA in sea urchin eggs that is destroyed at each
cleavage division.
Cell
33, 389-396 (1983).
discovery of cyclin.
blastula 6
definition 4
cell cycle
downstream events 14
early embryonic 1-22
definition 6
early studies 1
maternal stockpiles 6
model 17, 19
organization 15
photographs 3
protein synthesis requirement 10
suprression of G1 and G2 4
engine See cell cycle engine
MPF oscillation during 10, 12
transitions 15
cell cycle engine 12-20
autonomy in frog eggs 12
The
definition 14
transitions 15
Cyclin
classes 19
diversity 19
Cytoplasmic transfer experiments 8-11
downstream events
definition 14
eggs see frog-eggs, sea urchin-eggs, clam-eggs,
starfish-eggs, Drosophila melanogaster-eggs
frog
early embryonic cell cycle 4-16
eggs 12
cell cycle 4-16
cytoplasmic transfer experiments 8
life cycle 4-6
meiotic cell cycle 7-10
oocyte
cytoplasmic transfer experiments 8
oocytes 4-10
induction of meiosis by progesterone 6-10
interphase
downstream events 14
maturation
definition 8
maturation promoting factor see MPF
meiotic cell cycle 7
meiotic maturation
definition 8
mitosis
downstream events 14
induction by MPF 10, 12
MPF
activation by post-translational reactions 9
discovery 8, 9
mitosis-inducing activity 10, 12
oscillation during cell cycle 10, 12
protein synthesis and activation 10
role in cell cycle transitions 15
periodic proteins 17
polar body
definition 7
pre-MPF
discovery 9
Progesterone
induction of meiosis by 6-10
sea urchin eggs
cyclin discovery 17
South African clawed frog see frog
Xenopus laevis see frog
Figure 2-1 Interphase of the first cell cycle, the first mitosis, and the second cell cycle of
fertilized sea urchin eggs. Between interphase and mitosis, the chromosomes become
visible, the nucleus breaks down, and the spindle forms. All of these changes are
reversed as the cell proceeds into the next interphase.
Not available
Figure 2-2 Early embryonic and somatic cell cycles. Somatic cell cycles in frogs
typically last about 1 day and have a G1 and a G2. Twelve rapid divisions occur after
fertilization, after which the synchrony between the cell cycles of neighboring cells
breaks down.
Figure 2-3 Frog early development. As they emerge from the female frog, eggs are
fertilized and undergo 12 rapid cell divisions to produce the blastula, a hollow ball of
cells. The blastula undergoes complex structural rearrangements that ultimately give rise
to a tadpole.
Figure 2-4 Frog oogenesis, meiosis, and fertilization. Oocytes are born at the same size
as typical somatic cells. They replicate their DNA and then arrest as they grow in
diameter from 20 µm to 1 mm. Secretion of progesterone by the follicle cells that
surround the oocyte induces it to undergo the first meiotic division and enter the second.
The oocytes arrest in metaphase of meiosis II and emerge in this state as unfertilized
eggs. Fertilization overcomes the metaphase arrest and initiates the early embryonic cell
cycles.
Figure 2-5 Discovery of MPF. Oocytes induced to mature into unfertilized eggs by
treatment with progesterone are used to donate cytoplasm to untreated oocytes. The
transferred cytoplasm contains active MPF (maturation promoting factor), which induces
the recipient oocytes to enter meiosis. Maturation induces the activation of MPF in the
recipient oocyte, allowing it to act as a cytoplasmic donor that can induce meiosis in a
fresh round of recipient oocytes. Reference: Masui, Y. & Markert, C.L. J Exp Zool 177,
129-45 (1971).
Figure 2-6 MPF fluctuations in meiotic and mitotic cell cycles. Oocytes have low levels
of MPF activity. Progesterone induces the activation of MPF, leading to meiosis I. After
a brief decline, a second rise in MPF activity induces meiosis II, and the oocytes remain
arrested in metaphase of meiosis II with high levels of MPF. This arrest is overcome by
fertilization, which leads to a precipitous decline in MPF activity. Interphase of the first
mitotic cell cycle lasts about 60 minutes, while that of cycles 2 through 12 last about 15
minutes. Each mitosis lasts about 15 minutes and is initiated by the activation of MPF
and terminated by its inactivation. Reference: Gerhart, J., Wu, M. & Kirschner, M. J.
Cell Biol. 98, 1247-1255 (1984).
Figure 2-7 Induction of mitosis by MPF. Treating fertilized eggs with protein synthesis
inhibitors arrests them in interphase, but injecting partially purified MPF into the arrested
eggs induces them to enter mitosis. Reference: Newport, J.W. & Kirschner, M.W. Cell
37, 731-42 (1984).
Figure 2-8 MPF oscillates independently of DNA synthesis and spindle assembly. The
fluctuation of MPF activity in normally fertilized embryos (the control) is compared with
that of embryos fertilized in the presence of an inhibitor of DNA polymerization
(aphidicolin) or spindle assembly (nocodazole). The oscillations in the three sets of
embryos are identical, showing that the failure to complete DNA replication does not
influence the reactions that periodically activate and inactivate MPF. Reference:
Gerhart, J., Wu, M. & Kirschner, M. J. Cell Biol. 98, 1247-1255 (1984).
Figure 2-9 Cell cycle engine and downstream events. The cell cycle is divided into two
types of processes. MPF is part of the cell cycle engine, a biochemical machine that
produces cyclical oscillations in the activity of MPF and other key cell cycle regulators
that control downstream events. Active MPF induces the downstream events of mitosis,
which interact to assemble the mitotic spindle. The inactivation of MPF at the end of
mitosis induces the downstream events that lead to interphase, including chromosome
segregation, and cytokinesis. In early embryonic cell cycles, DNA replication and
duplication of the centrosome are consequences of the inactivation of MPF.
Figure 2-10 Organization of the early embryonic cell cycle. Each transition in the cell
cycle engine leads to coordinated changes that rearrange the cell. The cell remains in this
new state until the next transition occurs in the cell cycle engine. The activation of MPF
at the beginning of mitosis leads to the mitotic downstream events, which produce a cell
with a metaphase spindle. The inactivation of MPF induces the interphase downstream
events, which produce a G2 cell with replicated DNA and duplicated centrosomes
(MTOC).
Figure 2-11 Discovery of cyclin. The abundance of newly synthesized proteins was
measured during the first two cell cycles of fertilized sea urchin eggs. Most new proteins
increased in abundance steadily with time after fertilization. The abundance of cyclin,
however, increased during each interphase and declined abruptly at the end of each
mitosis. Reference: Evans, T., Rosenthal, E.T., Youngblom, J., Distel, D. & Hunt, T.
Cell 33, 389-396 (1983).
Figure 2-12 Early embryonic cell cycle model. The fluctuatation of cyclin abundance
and MPF activity in the early embryonic cell cycle suggests a flip-flop model for the cell
cycle engine. In interphase MPF is inactive, but the accumulation of cyclin leads to the
activation of MPF and entry into mitosis. In mitosis MPF is active, but MPF induces the
degradation of cyclin, leading to the inactivation of MPF and entry into interphase.