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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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reviews
  • 322 Nurse, P. (1990).  Universal control mechanism regulating onset of M-phase.  Nature 344, 503-508.  PubMed  
  • 2045 Mitchison, J. M. (1971). The Biology of the Cell Cycle (Cambridge: Cambridge University Press).
reviews
  • 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
  • 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
  • 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
  • 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
  • 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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