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Gene knockouts reveal new hierarchy of cell cycle proteins: CNIO researchers report in Nature engineering of mouse strains that shed new light on the role of Cdks in mammalian cell proliferation Madrid. 16 August 2007-. An article published in the August 16th issue of the journal Nature mainly carried out in the Barbacid lab at the Spanish National Cancer Research Centre (CNIO), demonstrates that the cyclin-dependent kinase Cdk1 is sufficient to drive the mammalian cell cycle. Basic Background Cell division, a process by which a cell – the parent cell – divides into two - daughter cells - is the most basic of biological processes. Without it, living organisms cannot develop and would remain as one-celled zygotes. The diversity of organisms just as their respective cell types is phenomenal, though this fundamental process has remained constant throughout evolution. In all eukaryotic organisms, the cell cycle requires the activation of cyclin-dependent kinases (Cdks).While Cdks are usually present throughout the entirety of the cell cycle, cyclins only synthesise at determined phases of each cell division or cycle. The discovery of these basic processes earned Paul Nurse, Timothy Hunt and Lee Hartwell the Nobel Prize for Medicine and Physiology just six years ago. When a cell receives the signal to divide it abandons its rested stated, know as phase G0 and enters into the G1 phase of the cell cycle. In G1 the cell prepares to duplicate its genome producing one identical copy of its DNA; phase S. The journey continues to phase G2 to mitosis – the stage in which a cell duplicates its chromosomes to generate two identical cells. This is then followed by cytokinesis which divides the cytoplasm and cell membrane, resulting in two identical cells with an equal distribution of organelles and other cellular components. Mitosis followed by cytokinesis complete the division of the mother cell into two identical daughter cells, each with the genetic equivalent of the parent cell. The Tradition The principle difference in cell division between unicellular and multicellular organisms is determined by Cdks. In unicellular organisms just one sole Cdk (Cdk2, Cdk8, or Cdk1) controls the entire process and can sequentially associate itself with the different cyclins throughout the four phases of the cell cycle. Multicellular organisms however, such as mammals, require multiple Cdks specific to each phase. In the past, it has been widely accepted that mammalian cells use up to five different Cdks to complete the cell cycle. In sequence these are Cdk4, Cdk6, Cdk3, Cdk2 and Cdk1. According to this widely accepted model, Cdk4 and Cdk6, which interact with D cyclins, are essential for the G1 phase. S phase is lead by Cdk2 that sequentially binds with cyclins E and cyclins A to accomplish DNA duplication. Cdk1 interacts with cyclin A during phase G2 and finally the complexes formed by Cdk1 and cyclins B have been considered as responsible for proceeding through mitosis. Very little has been reported about Cdk3 since laboratory mice lack functional Cdk3, and it has only therefore been studied in human cells in vitro, suggesting a similar role to that of Cdk2. The Turning Point This previously affirmed series of events and processes however was first questioned four years ago when the Experimental Oncology Group at the CNIO, directed by Mariano Barbacid, published a study in Nature Genetics revealing that Cdk2, assumed to be essential for genome replication in phase S, is not necessary since mice cell types proliferate in the absence of this enzyme. Similar studies were also reported in Current Biology by the Kaldis lab at NCI. A further study followed from the Barbacid group - this time published in Cell. They demonstrated that Cdk4 and Cdk6 were not essential for phase G1 of the cell cycle or for any other phase, but, they were necessary for the division of just one cell type – haematopoietic (blood) cells. In May this year the Barbacid lab also reported in a new journal, Mol. Oncology, the generation of mice in the absence of Cdk4 and Cdk2 – the two kinases that were previously considered as being principally responsible for all phases of the cell cycle (with the exception of mitosis) in the majority of cells. To the surprise of many, these mice completed embryonic development and reached birth. These mice once again manifested specific problems in certain cell types such as cardiomyocytes, but not in the basic cell cycle process. CNIO researchers have also shown that eliminating both kinases in the liver of adult mice, through sophisticated genetic recombination, did not have any consequences in hepatocytes lacking CdK4 and CdK2, and proliferated as efficiently as normal heptocytes. These findings suggest once more the participation of Cdks in cellular proliferation processes in specialised cells, but not in the basic cell cycle. These results are at variance with those of the Kaldis lab reported in Developmental Cell. Similar mice generated in this lab did not develop to term and their cells did not proliferate in vitro. The reasons for this severe phenotype remain to be determined. Now, the Barbacid team led by David Santamaría in collaboration with other investigators from the CNIO (M. Malumbres), the University of Bordeaux (P. Dubus) and the Western General Hospital of Edinburgh (K. Newton and J. Cáceres) report in the August 16th issue of Nature that mouse embryos lacking in all interphase Cdks (Cdk2, Cdk3, Cdk4 and Cdk6) can complete the cell cycle. More importantly, embryos with Cdk1 alone undergo organogenesis which shows that such embryos cannot only complete embryonic development assuming maximum cell division activity (20 million cells produced in two weeks), but can also produce all cell types, tissues and organs of an adult organism. As suspected, embryos with only Cdk1 do not complete embryonic development since they do not produce blood cells through the absence of Cdk4 and Cdk6. The work carried out by David Santamaria and colleagues at the CNIO goes further by demonstrating that Cdk1, in the same way as yeasts and other unicellular organisms, is essential to drive cell division. In collaboration with researchers in the UK, CNIO scientists have generated mice without Cdk1 and showed that in the absence of this enzyme embryos fail to develop even to the morula stage (embryos with 16-64 cells), suggesting that Cdk1 is essential for the first embryonic divisions. In conclusion, these findings, as with previous aforementioned work of the Barbacid lab, demonstrate that mammalian cells are not mechanistically too different from unicellular organisms and that one Cdk alone – Cdk1 – can bind to all cyclins and drive the cell cycle. CNIO researchers have also shown that the role of Cdk1 in the cell cycle is far more involved than its function in mitosis, just as that occurring in unicellular organisms. Equally, it seems ever more evident that generating multiple Cdks in superior organisms – such as mammals – derives from the need to provide specialized cells with the sufficient Cdk kinase activity to enable cells to divide according to the specific needs of organisms. Toward Targets These studies are critical to developing specific therapies to treat tumours in humans. Cdks have been the object of much interest as therapeutic targets from within the entire pharmaceutical industry since cancer as well as other diseases are caused by aberrant cell proliferation. Unfortunately to date, no Cdk inhibitor has achieved the results necessary to advance further than phase II in clinical trials. A more precise understanding of how each Cdk contributes to driving cell division should help us to determine what strategy to follow to ensure that the inhibition of one or more Cdk can in turn have an inhibiting effect on the proliferation of tumour cells without effecting normal cells of cancer patients. Forthcoming studies will allow us to validate whether Cdks are targets of therapeutic interest in cancer - once and for all. #### EDITOR’S NOTES 1) The Spanish National Cancer Research Centre (CNIO) is one of the few European Cancer Research Centres of international excellence that effectively combines basic and applied research. For more detailed information surrounding the CNIO, its rapidly expanding research programmes, list of publications, international conferences and symposia, and the latest Scientific Report please visit: www.cnio.es or contact us directly: 2) David Santamaría Centro Nacional de Investigaciones Oncológicas Melchor Fernández Almagro 3 E-28029 Madrid Tel: +34 91 2246900, Fax: +34 91 2246980 Email: [email protected]