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GREAT EXPERIMENTS
The discovery of cdc2 as the key regulator of the cell cycle
Paul Nurse
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Introduction
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The two major events of the eukaryotic
cell cycle are S phase, when chromosomes are replicated, and M phase or
mitosis, when the replicated chromosomes are segregated into the two
daughter cells at cell division. By the 1970s these events had been
well described, but little was known about how the timing of either
phase was controlled during the cell cycle. The most popular idea was
that undefined "division proteins" accumulated during the cell cycle,
eventually generating a structure which was required for the onset of M
phase and cell division (2045). Understanding significantly
improved between the late 1970s and the early 1990s with the
elucidation of the molecular mechanisms that regulate the onset of both
S phase and M phase. These studies led to the identification of the
cyclin dependent kinases (CDKs) as the core cell cycle regulators
conserved in all eukaryotes from yeast to human beings (322).
A key set of experiments which led to this realization centered on
demonstrating that the cdc2 protein controls entry into mitosis in
fission yeast, is functionally conserved in humans, and is a component
of an M phase-promoting activity from frog eggs called MPF.
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Background
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In the early 1970s, two independent lines
of inquiry into control of the cell cycle began. Conducted in different
experimental systems and using completely different techniques, both
approaches identified cellular components that controlled entry into
mitosis. One, MPF, was an activity identified by transferring cytoplasm
between frog eggs. The other was a network of regulatory genes
identified genetically in fission yeast and focusing on the cdc2
gene. Although they acted at the same cell cycle transition, any
possible relationship between these two factors was uncertain. This was
in part because of hesitation to believe that the control of the cell
cycles of single celled and multicellular eukaryotes could be related,
and in part because of the considerable differences in the means by
which the two components had been identified.
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Figure 1
Variation in the level of MPF during the mitotic cycle suggested that it might be a regulator of mitosis.
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MPF was discovered by Yoshio Masui while
studying the mechanism by which hormones induce meiosis in the oocytes
of amphibians, a system he chose largely because the large size of the
oocytes makes them easy to manipulate (see The discovery of MPF).
He found that injection of cytoplasm from eggs of the frog Rana pipiens
induces oocytes to leave the G2 phase of the cell cycle (in which they
are naturally arrested) and advance through the first meiotic division,
initiating their maturation into eggs (1582). He referred to
the activity within the cytoplasm which caused maturation as
"maturation promoting factor" (hence the name MPF).
A similar activity was subsequently described in Xenopus laevis,
another species of frog, and its level was found to oscillate in synchrony
with the mitotic cell cycle of dividing Xenopus eggs,
peaking once per cycle at M phase, as shown in Figure 1 (1570).
These observations led to the proposal that MPF induces onset of M
phase in both meiosis and mitosis, and suggested that the oscillations
in its activity might drive the cell cycle. As a first step towards
defining MPF in molecular terms Masui also developed extracts of Rana
eggs in which added sperm nuclei would replicate their DNA and enter M phase (1572).
This in vitro cell cycle system was later extended to Xenopus egg extracts,
providing an assay for components that could drive the cytoplasm into M phase.
Despite the availability of an in vitro
system and the expenditure of great effort on the part of several
laboratories, MPF resisted purification and molecular characterization
for years after it was recognized as significant.
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On the other front was the genetics.The
discovery of genes that might participate in cell cycle control was
initially made by Lee Hartwell working with budding yeast (2038).
He isolated mutants that halted at specific points within the cell
cycle, each mutant defining a gene whose function was required once per
cell cycle. Many such genes existed, and they revealed numerous points
throughout the cell cycle at which it could be blocked. Called "cell
division cycle"(cdc) mutants, they were of necessity conditional,
able to grow at normal but not elevated temperature.
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Figure 2
Wee mutants are considerably smaller than normal cells and can be identified just by looking.
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My own laboratory extended the genetic approach to fission yeast,
initially isolating cdc mutants and later mutants which
underwent cell division at a reduced size compared with normal,
which we called "wee"
mutants. The first of these mutants was isolated entirely by accident
in Scotland (accounting for their name!) during a visual screen for cdc mutants (2044).
Figure 2 shows that they are perceptibly smaller than normal cells.
The wee mutants attracted our attention because cells that
divide at a smaller size than normal do so because they are advanced prematurely
into an otherwise normal mitosis and cell division. The ability to advance mitosis could occur only if the wee
mutants were altered in the process controlling the initiation of
mitosis, and they were thus particularly interesting. Our logic in
arriving at this conclusion was as follows. A decrease in the rate at
which cells traverse the cell cycle, or a complete block in the cycle,
requires only that the inactivated component participate in any cell
cycle specific event or structure. It does not indicate that in wild
type cells the component is rate limiting for passage through the
cycle. Rather, it indicates only that any required component can be
made limiting if its function is sufficiently reduced. Acceleration
through part of the cell cycle, however, can occur only if a function
that is rate limiting for the cycle in normal cells is enhanced in the
mutant. The wee mutants thus identified components whose
function was not to carry out any of the mechanical or structural
events of mitosis (e.g., spindle formation or chromosome separation),
but was instead to decide when to initiate the process.
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Figure 3
In fission yeast the cdc2 gene exerts the primary influence that controls entry into mitosis. The cdc25 and wee1 genes influence the transition by interacting with cdc2.
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The fact that more than one gene could
mutate to give the wee phenotype suggested that the decision to enter
mitosis was made not by a single component but by a regulatory network.
We initially identified three genes as part of this network (322).
Among them the most interesting was cdc2 because it could be mutated
in two different but complementary ways: recessive ts cdc2 mutants failed
to enter mitosis, whilst dominant wee cdc2
mutants entered mitosis prematurely. Because recessiveness usually
indicates that a gene product is either missing or nonfunctional, and
dominance that its activity is increased, these experiments strongly
suggested that cdc2p is a positive regulator of mitosis. Further
genetical analysisdemonstrated that the twoother genes, wee1
and cdc25, functioned upstream of cdc2, with wee1p acting
as a negative regulator and cdc25p as a positive regulator. This network is shown in Figure 3.
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The cdc2 gene was isolated functionally by
transforming a plasmid library of fission yeast genes into a ts cdc2
mutant strain. The plasmid-borne gene was selected by its ability to
complement the mutant chromosomal gene; only cells taking up a plasmid
containing the cdc2 gene could divide and form colonies at the
restrictive temperature of the ts cdc2 mutants. The sequence of the cdc2
gene was subsequently shown to have similarity with protein kinases.
Antibodies raised against the cdc2 protein were used to
immunoprecipitate the protein from fission yeast cells and to
demonstrate that it had protein kinase activity. It was concluded from
these experiments that cdc2p is a protein kinase that regulates the
onset of mitosis in fission yeast, and that its activity is controlled
by a regulatory network including wee1p and cdc25p.
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The key experiments
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The stage was now set to ask if the
mechanism controlling the onset of mitosis might be the same in all
cells. At that time it was not fully appreciated that many eukaryotic
cellular functions are highly conserved, and it was thought rather
unlikely that controls over the cell cycle could be the same in a
simple unicellular organism like yeast and in human cells. On the other
hand many mechanisms of biochemistry and molecular biology had been
found to be conserved, so why not processes in cell biology as well? To
test this possibility Melanie Lee in my laboratory decided to look for
a human homologue of cdc2. Her initial approach was to screen
for a human gene with structural similarity to cdc2,
using either low stringency Southern blotting to detect DNA sequence
similarity or a phage expression human gene library and cdc2p
antibodies to detect protein sequence similarity. Both approaches
identified human protein kinases, but these had little sequence
similarity to cdc2 outside the kinase catalytic domain.
This raised the question of how a true human homologue of cdc2
could be unambiguously identified, given the wide evolutionary
divergence between the two organisms and the presence of many hundreds
of protein kinases present in human cells.
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Figure 4
cdc2 ts cells elongate but cannot enter mitosis and divide when grown at the nonpermissive temperature.
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Figure 5
A plasmid library of human genes is introduced into cdc2 ts cells. After transformation the cells are plated out at the nonpermissive temperature for the cdc2 ts mutant. Only cells which have received a human gene which can functionally replace the cdc2 gene will be able to divide and produce colonies.
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To overcome this problem Melanie tried a different approach.
She set out to clone a human version of cdc2 by asking for
genes able to complement a ts cdc2 mutant. These mutants elongated
but failed to divide at the nonpermissive temperature, as shown in Figure 4. If a human cdc2
gene existed, then its introduction into these cells would enable them
to divide again. The practical aspects of this approach are shown in Figure 5,
and are much the same as those we had used to clone the yeast cdc2 gene initially.
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Melanie's rather bold approach required the human gene to be functionally equivalent to cdc2
rather than being merely structurally similar. This was a demanding
requirement because it meant that the human version of the protein
would have to be capable of not only performing the same functions as
the yeast version, but also of responding to the same regulatory inputs.
I think we were both surprised, although very agreeably so, when Melanie managed
to isolate a human cDNA which complemented a ts cdc2 mutant.
There then followed a frantic flurry of experiments to ensure that the cDNA
we had isolated really encoded a true human cdc2 homologue. We gradually
eliminated the possibilities that the cDNA had somehow been contaminated by the fission yeast cdc2
gene, or that we had cloned another gene that could somehow compensate
for the absence of cdc2 function (an "extragenic suppressor"). These
controls seemed to go painfully slowly, but with the elimination of
each alternative explanation our excitement grew to the point at which
it was almost unbearable as we realised that there might indeed be a
human cdc2 gene. We sequenced the clone, and one
memorable morning in the lab the protein sequence encoded by the human
cDNA appeared on the computer screen and was shown to have a
dramatically high 63% identity with the fission yeast cdc2p. This
similarity, together with the fact that the human cDNA could fully
substitute for the fission yeast cdc2 gene, strongly argued
that the cDNA was derived from a human CDC2 gene and implied that
the basic mechanism controlling the onset of mitosis is conserved from yeast to humans (2041).
Further support that there was indeed a protein similar to cdc2p in
human cells was made when antibodies raised against fission yeast cdc2p
were found to detect a 34 kDa protein kinase in human cells (2036).
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Our discovery demonstrated that a
specific protein which regulated entry into mitosis was very likely to
be present in all eukaryotes. The question remained as to how cdc2p
might be related to MPF, which acts at the same cell cycle transition
and is also widespread. Nothing we knew about them made it a certainty
that they were the same thing. The evidence allowed that possibility,
but it was also possible that they were different components acting in
a pathway, or even that they were parallel inputs which could initiate
mitosis independently of one another. The answer came as soon as we
knew the molecular basis of MPF. Shortly after our result, Jim Maller's
group succeeded in purifying MPF using the Xenopus in vitro
cell cycle assay mentioned earlier and found the activity to be
associated with two proteins with molecular weights of 32 and 45 kDa
(1587). Immunoblotting and immunoprecipitation experiments using
antibodies raised against cdc2p demonstrated that the 32 kDa protein
was the Xenopus equivalent of cdc2p (829). A similar
conclusion was reached using a protein from yeast called suc1p, which
had been found to bind cdc2p strongly. Beads with suc1p attached were
capable of depleting a Xenopus extract of MPF, suggesting that this
activity was associated with a cdc2p-like protein (828).
MPF was also highly purified from starfish and shown to contain two proteins
of 34 kDa and 47 kDa, the smaller one again being cdc2p (831).
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The identity of the larger 45-47 kDa
component of MPF proved to be no less significant; it was a cyclin.
This observation unified the yeast and frog approaches to the cell
cycle with a third, independent approach which had started about a
decade later but which had immediately identified particular molecules
as possible cell cycle regulators.
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The cyclins had initially been
identified as a small group of proteins in dividing sea urchin eggs
which accumulated during each cell cycle and were then abruptly and
completely destroyed at the end of each M phase. As a consequence the
amount of the proteins "cycled" with the same period as the cellcycle,
making them candidates for components which controlled cell cycle
transitions. By the time MPF was purified a number of experiments had
implicated cyclins in the control of M phase. Injection of clam cyclin
mRNA into Xenopus oocytes induced M phase entry, and ablation of cyclin
mRNA in the oocytes blocked M phase onset when they were treated with
hormones which normally induced meiosis (2043). A general
significance for cyclins in cell cycle regulation in unicellular eukaryotes
was suggested when Cdc13, a fission yeast gene required for onset of
mitosis, was shown to encode a cyclin (2034; 2037).
Thus, the observation that MPF is a complex of cdc2p and a cyclin
brought together the results of three unrelated approaches that had
resulted in regulators of M phase. The convergence of different
approaches in three such widely different organisms strongly suggested
that the result might apply in all eukaryotes. The evidence that such a
complex is indeed a universal controller of entry into mitosis mounted
when the 47 kDa component of purified starfish MPF was microsequenced
and also found to be a cyclin (2039), and when a cyclin gene
was cloned from human cells and the encoded cyclin shown to be associated with cdc2p (2042).
Association with a cyclin was subsequently shown to be required for
cdc2p to possess kinase activity. cdc2p and related proteins are thus
called "cyclin dependent kinases," or CDKs.
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A postscript to this work concerns the
similarity of the M phase-promoting CDK activity to a protein kinase
that had been characterized much earlier than the work described here.
The usual substrate used to monitor MPF activity is H1 histone, and an
H1 histone kinase activity had been identified in the mould Physarum
as a cell cycle regulated enzyme peaking at mitosis (2035).
When it was added to the surface of Physarum nuclei they were advanced
into mitosis. Years later this protein kinase was revisited and also shown to be cdc2p
(2040), and so this earlier work foreshadowed the later biochemical experiments
into M phase control carried out using Xenopus and starfish. At the time, however,
its generality was not appreciated.
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So the picture that emerged from this
work in late 1989 was of a single two component complex that controls
entry into both mitosis and meiosis in a range of eukaryotes from
fission yeast through clams and starfish to Xenopus and
humans. This conclusion brought about a satisfying convergence between
genetical and biochemical approaches to cell cycle control. Although at
least some investigators had suspected early on that the two approaches
might be detecting related activities, there was no obvious means by
which to test the idea experimentally. This problem was solved once
each approach had yielded a molecule: yeast genetics ultimately
identifying cdc2p as performing the rate-limiting step controlling M
phase onset, and biochemistry being used to purify MPF from extracts of
Xenopus and starfish. Once these were accomplished
it was possible to ask a well defined question: does MPF contain cdc2p?
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With the cell cycle, as in many other
cases, studies in model organisms paved the way to show that similar
controls operated in human cells. It is probably safe to say that the
problem would not have been solved without model systems that provided
strategic experimental advantages. It is hard to imagine how it could
ever have been solved using human cells alone, at least over a
reasonable time scale. Genetics with human cells is difficult, and it
is problematic to grow enough of them to perform the scale of
biochemistry that was required to purify MPF.
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Present significance
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These initial experiments heralded in a
new era of highly productive cell cycle research which continues today.
Work, mainly with budding and fission yeasts, showed that CDK
activities closely related to MPF also regulate the onset of S phase,
demonstrating that CDKs control both S phase and M phase. This general
conclusion was then shown to also apply to multicellular eukaryotic
organisms. These experiments led to the present view that CDKs act as
core cell cycle regulators, driving cells through the major events of
the cell cycle which bring about the replication and segregation of the
chromosomes, and ensuring that these events occur only once in each
cell cycle (835). These basic elements of cell cycle control
are conserved in all eukaryotes, suggesting that they act as universal
cell cycle regulators and have origins that are probably coincident
with the emergence of eukaryotic cells 1500-2000 million years ago (for
a discussion of our current understanding of the cell cycle see Cell cycle and growth regulation).
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In multicellular eukaryotes there are a
number of different CDK protein kinase and cyclin subunits, and
different members of each family act at the onset of S phase and M
phase. Other CDK activities function earlier in the cell cycle, and
regulate both the growth of the cell and progression through G1. Of
particular importance in this regard is CDK4/cyclin D, which is part of
a network including the p16 CDK inhibitor, the Retinoblastoma protein
(Rb), and the transcription factor E2F, a network which is frequently
disrupted in cancerous cells. CDK regulation also plays an important
role in the checkpoint controls maintaining genomic stability, and a
breakdown of these controls generates genetic damage which is likely to
contribute to the transformation of a normal cell to a cancerous cell (843).
Thus CDKs are important for understanding not only normal cell cycle
regulation but also the molecular mechanisms underlying cancer.
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The author
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Paul Nurse became Director General of the Imperial Cancer Research Fund in
1996 after having served for three years as Director of Research. He
also heads Imperial Cancer's Cell Cycle Laboratory, a research group
which studies the genes that prompt cells to divide. Paul is probably
best known for his contribution to the discovery of the mechanism which
controls cell division in most living organisms. Working with fission
yeast he discovered a gene which controls the process of cell division,
and he was also the first to demonstrate its human counterpart, so
illustrating the universal nature of this mechanism and its profound
implications for the field of cancer research.
Paul was born in Norfolk, England in 1949 and was educated at the
Universities of Birmingham (BSc 1970) and East Anglia (PhD in Cell
Biology 1973). He has been a research fellow and professor at several
other universities including Bern, Edinburgh, Sussex and Oxford. In
1989 he was elected a Fellow of the Royal Society, in 1995 a Foreign
Associate of the US National Academy of Sciences and in 1999 an
Honorary Member of the Royal College of Physicians.
He has been honoured with awards and medals by numerous institutions
in recognition of his contributions to medical research. In 1997 he
received the General Motors Cancer Research Foundation Alfred P Sloan
Jr. Prize and Medal, and in 1998 he shared the Albert Lasker Award for
Basic Medical Research. Most recently he received the 2001 Nobel Prize
in Physiology or Medicine along with Lee Hartwell and Tim Hunt.
Paul has served on many national committees and is presently a
member of the Council for Science and Technology, which advises the
Prime Minister and the Cabinet. He is also a member of the
international Advisory Boards of the Sloan Kettering Cancer Center in
New York, ISREC in Lausanne, Switzerland and a member of the Scientific
Council of the Institut Curie in Paris. He is the author of many
scientific papers, and has served on the editorial board of several
journals.
In 1999 Paul received a Knighthood for services to cancer research
and cell biology. He lives with his wife and two daughters in Oxford.
Paul Nurse FRS
Director-General
Imperial Cancer Research Fund
44 Lincoln's Inns Fields
London WC2A 3PX, UK
Phone: 44 (0)20 7269 3436
Fax: 44 (0)20 7269 3610
E-mail: p.nurse@icrf.icnet.uk
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Last Revised on September 10, 2004
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322 Nurse, P.
(1990).
Universal control mechanism regulating onset of M-phase.
Nature 344, 503-508.
PubMed
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2045 Mitchison, J. M.
(1971).
The Biology of the Cell Cycle (Cambridge: Cambridge University Press).
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828 Dunphy, W. G., Brizuela, L., Beach, D., and Newport, J.
(1988).
The Xenopus cdc2 protein is a component of MPF, a cytoplasmic regulator of mitosis.
Cell 54, 423-431.
PubMed Journal
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829 Gautier, J., Norbury, C., Lohka, M., Nurse, P., and Maller, J.
(1988).
Purified maturation-promoting factor contains the product of a Xenopus homologue of the fission yeast cell cycle control gene cdc2+.
Cell 54, 433-439.
PubMed Journal
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831 Labbe, J. C., Picard, A., Peaucellier, G., Cavadore, J. C., Nurse, P., and Doree, M.
(1989).
Purification of MPF from starfish: identification as the H1 histone kinase p34cdc2 and a possible mechanism for its periodic activation.
Cell 57, 253-263.
PubMed Journal
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835 Hayles, J. et al.
(1994).
Temporal order of S phase and mitosis in fission yeast is determined by the state of the p34cdc2 mitotic B cyclin complex.
Cell 78, 813-822.
PubMed Journal
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843 Weinert, T. A., and Hartwell, L. H.
(1988).
The RAD9 gene controls the cell cycle response to DNA damage in S. cerevisiae.
Science 241, 317-322.
PubMed
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1570 Gerhart, J., Wu, M., and Kirschner, M.
(1984).
Cell cycle dynamics of an M-phase-specific cytoplasmic factor in Xenopus laevis oocytes and eggs.
J. Cell Biol. 98, 1247-1255.
PubMed
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1572 Lohka, M. J. and Masui, Y.
(1983).
Formation in vitro of sperm pronuclei and mitotic chromosomes induced by amphibian ooplasmic components.
Science 220, 719-721.
PubMed
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1582 Masui, Y. and Markert, C. L.
(1971).
Cytoplasmic control of nuclear behavior during meiotic maturation of frog oocytes.
J. Exp. Zool. 177, 129-145.
PubMed
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2034 Booher, R. and Beach, D.
(1988).
Involvement of cdc13+ in mitotic control in S pombe: possible interaction of the gene product with microtubules.
EMBO J. 7, 2321-2327.
PubMed
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2035 Bradbury, E. M., Inglis, R. J., and Matthews, H. R.
(1974).
Control of cell division by very lysine rich histone (F1) phosphorylation.
Nature 247, 257-261.
PubMed
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2036 Draetta, G., Brizuela, L., Potashkin, J., and Beach, D.
(1987).
Identification of p34 and p13, human homologs of the cell cycle regulators of fission yeast encoded by cdc2+ and suc1+.
Cell 50, 319-325.
PubMed Journal
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2037 Hagan, I., Hayles, J., and Nurse, P.
(1988).
Cloning and sequencing of the cyclin-related cdc13+ gene and a cytological study of its role in fission yeast mitosis.
J. Cell Sci. 91, 587-595.
PubMed
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2038 Hartwell, L. H., Culotti, J., and Reid, B.
(1970).
Genetic control of the cell-division cycle in yeast. I. Detection of mutants.
Proc. Natl. Acad. Sci. USA 66, 352-359.
PubMed
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2039 Labbe, J. C., Capony, J. P., Caput, D.,
Cavadore, J. C., Derancourt, J., Kaghad, M., Lelias, J. M., Picard, A.,
and Doree, M. (1989). MPF from starfish oocytes at first meiotic
metaphase is a heterodimer containing one molecule of cdc2 and one
molecule of cyclin B. EMBO J. 8, 3053-3058. PubMed
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2040 Langan, T. A., Gautier, J., Lohka, M., Hollingsworth, R., Moreno, S., Nurse, P., Maller, J., and Sclafani, R. A.
(1989).
Mammalian growth-associated H1 histone kinase: a homolog of cdc2+/CDC28 protein kinases controlling mitotic entry in yeast and frog cells.
Mol. Cell Biol. 9, 3860-3868.
PubMed
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2041 Lee, M. G. and Nurse, P.
(1987).
Complementation used to clone a human homologue of the fission yeast cell cycle control gene cdc2.
Nature 327, 31-35.
PubMed Journal
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2042 Pines, J. and Hunter, T. (1989).
Isolation of a human cyclin cDNA: evidence for cyclin mRNA and
protein regulation in the cell cycle and for interaction with p34cdc2.
Cell 58, 833-846. PubMed Journal
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2043 Swenson, K. I., Farrell, K. M., and Ruderman, J. V.
(1986).
The clam embryo protein cyclin A induces entry into M phase and the resumption of meiosis in Xenopus oocytes.
Cell 47, 861-870.
PubMed Journal
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2044 Nurse, P.
(1975).
Genetic control of cell size at cell division in yeast.
Nature 256, 547-551.
PubMed
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©Jones and Bartlett Publishers (2007)
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