Cell Cycle Research Papers

Leland Hartwell, Sir Paul M. Nurse and R. Timothy Hunt

In 2001 the Nobel Foundation celebrated its one hundredth anniversary and will be hosting a banquet in December for all Nobel laureates. Following the 2001 award of the Nobel prize in Physiology or Medicine to three cell biologists, the ranks at the banquet will be swelled by Leland Hartwell, president and director of the Fred Hutchison Cancer Research Center, Seattle, Sir Paul Nurse, director-general of the ICRF in London and Timothy Hunt, also from ICRF (see pictures). These three researchers received their prize for outstanding contributions to the study of the eukaryotic cell cycle. Hartwell both identified a particular class of genes that control the cell cycle, including the gene that controls 'start', and introduced the concept of checkpoints. Nurse received his award for the identification, cloning and characterization of cyclin-dependent kinase (CDK) in yeast and for showing that the function of CDK is conserved in higher eukaryotes. Hunt's award was for his discovery of the cyclins some 10 years ago and for demonstrating that cyclins are degraded during the cell cycle.

As all cell biologists are aware, cell division must be tightly controlled to prevent the formation of developmental defects or cancer, and understanding the normal life cycle of cells is crucial for the development of new cancer treatments. The study of cell division is becoming increasingly multidisciplinary, however, and many new researchers in the field may not be as familiar with the key discoveries as others. So Nature Cell Biology, in collaboration with Nature Reviews Molecular Cell Biology, Nature Reviews Cancer and Nature, is pleased to welcome you to our first supplement and accompanying webfocus — 'Milestones in Cell Division'.

Milestones in cell division

The printed supplement contains 23 specially selected 'milestones' written by editors from the four participating journals and other Nature Publishing Group journals. Each milestone represents an important discovery, or set of discoveries, in the field, and together they give an overview of the history of cell division. They were selected with the help of more than 50 leading researchers in the field of cell division and each article discusses a paper or group of papers that forwarded the understanding of cell division in eukaryotes. For example, the Nobel prizewinning work of Nurse, Hartwell and Hunt is described in Milestones 5, 9, 11, 12 and 14.

In the printed supplement you will also find a small selection of published pieces in the field of cell division from all four journals. A much larger selection can be found on the Milestones in Cell Division webfocus site (www.nature.com/celldivision), which, as well as the milestones themselves, contains nearly 50 carefully selected reviews, articles, brief communications, News and Views and related material from all four journals.

The webfocus site is available free of charge to all visitors from December 2001 to June 2002 and contains the milestones, details of all the advisors used in the project and the collection of published material. The website will be updated on a monthly basis.

We hope you enjoy this first Nature Cell Biology supplement and will take time to explore the related website. For more information on the Milestones project read the editorial in the supplement and the related pieces on the website. We are also grateful to our sponsors Boehringer Ingelheim for their support of this project.

All textbooks describe the cyclin-dependent kinase complex as the one and only/exclusive regulator of the eukaryotic cell cycle. But now University of Groningen scientists have found evidence that a metabolic oscillator acts as the "conductor" of cell division. Their results were published online in the journal Molecular Cell on December 15.

Cells go through repetitive cycles of DNA duplication, growth, and cell division. These cycles require the careful coordination of cell-processes checkpoints that prevent cells from dividing when something -- DNA duplication, for example -- has gone wrong. The cyclin-dependent kinase complex was identified as the regulator of these cell cycles, and in 2001 the Nobel Prize for Physiology or Medicine was awarded for this discovery.

"But there were signs that this wasn't the complete story," says University of Groningen system biologist Matthias Heinemann. One sign was the fact that cells can divide, even when parts of the cyclin-dependent kinase complex are removed. Heinemann reasoned that metabolic oscillations might set the pace for cell division. "We knew that metabolism often oscillated in synchrony with the cell cycle. So maybe, this was an autonomous control mechanism."

Oscillator

Heinemann studied budding yeast cells cultivated in microfluidic channels. With that method, single cells could be monitored for days under the microscope. By using fluorescence techniques, it was possible to measure the concentration of two markers of metabolism: the electron carrier NADH and the energy carrier ATP. These molecules showed clear oscillatory patterns, rhythms that usually beat in synchrony with the cell cycle. Heinemann added, "But we also noticed that occasionally cells did not divide, and that these cells still showed metabolic oscillations."

So metabolism turned out to be a cell cycle-independent oscillator, which would oscillate fast if cells were well fed; poor nutrition, on the other hand, reduced the pace. "We argue that metabolism and the cyclin-dependent kinase complex are coupled oscillators, which together orchestrate the growth and division of eukaryotic cells." Or, in other words, the cyclin-dependent kinase complex is the orchestra, while the metabolic oscillations beat the rhythm, like a conductor does.

Compromise

"But when metabolism is slowed down or sped up too much, the cell cycle can't keep up and stops," says Heinemann. Both oscillations have their own natural frequency, and, under normal circumstances, these two oscillations are coupled and compromise with each other at a common frequency, which then governs the cell division process. Further experiments showed that the metabolic and the cell cycle oscillators could in fact be uncoupled.

The overall picture Heinemann and his colleagues have sketched in the Molecular Cell article is a system, in which the metabolic oscillator pulls the cyclin-dependent kinase complex through its cycle and dynamically gate the occurrence of the different cell cycle events.

New perspective

Biologists may have to change the way they view cell cycle regulation. "The current view is too narrow and cannot explain why cells still divide when part of the cyclin-dependent kinase complex is removed." A leading role played by metabolism also makes sense from an evolutionary perspective: "You would expect the earliest cells or proto-cells to have a simple control system to regulate division, and metabolism would be the obvious candidate." This new perspective could eventually be of clinical significance. "Most tumor cells have a very high metabolism. Interfering with metabolic processes could be a way to stop them from proliferating."


Story Source:

Materials provided by University of Groningen. Note: Content may be edited for style and length.


Journal Reference:

  1. Alexandros Papagiannakis, Bastian Niebel, Ernst C. Wit, Matthias Heinemann. Autonomous Metabolic Oscillations Robustly Gate the Early and Late Cell Cycle. Molecular Cell, 2016; DOI: 10.1016/j.molcel.2016.11.018


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University of Groningen. "New research paper challenges dogma of cell cycle control." ScienceDaily. ScienceDaily, 15 December 2016. <www.sciencedaily.com/releases/2016/12/161215143511.htm>.

University of Groningen. (2016, December 15). New research paper challenges dogma of cell cycle control. ScienceDaily. Retrieved March 10, 2018 from www.sciencedaily.com/releases/2016/12/161215143511.htm

University of Groningen. "New research paper challenges dogma of cell cycle control." ScienceDaily. www.sciencedaily.com/releases/2016/12/161215143511.htm (accessed March 10, 2018).

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