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Re: Cyclin- Nobel to Three Biologists

By Sean Henahan, Access Excellence

Seattle, WA (10/12/01)- Three biologists share this year's Nobel Prize in Physiology or Medicine for helping to unlock the secrets of the cell cycle, findings with broad implications in biology and medicine. Two British researchers, R. Timothy Hunt and Paul M. Nurse, both at the Imperial Research Cancer Foundation, will share the prize with Leland H. Hartwell of the Fred Hutchinson Cancer Research Center in Seattle.

In the first phase (G1) the cell grows. When it has reached a certain size it enters the phase of DNA-synthesis (S) where the chromosomes are duplicated. During the next phase (G2) the cell prepares itself for division. During mitosis (M) the chromosomes are separated and segregated to the daughter cells, which thereby get exactly the same chromosome set up. The cells are then back in G1 and the cell cycle is completed.

This year's Nobel Laureates discovered mechanisms controlling the cell cycle. CDK-molecules and cyclins drive the cell from one phase to the next. The CDK-molecules can be compared with an engine and the cyclins with a gear box controlling whether the engine will run in the idling state or drive the cell forward in the cell cycle.

The three scientists each contributed key insights into the molecular processed that drive the cell division in all eukaryotic organisms, from the lowly yeast Saccharymyces cerevisiaeto the Homo Sapiens.

More than twenty years ago Dr. Hartwell, began conducting key experiments with baker's yeast- Saccharymyces cerevisiae- that revealed the genetic basis of cell division. His work revealed that the basic molecular mechanisms governing cell division in yeast are identical to those at work in more advanced organisms. Indeed, thanks to Hartwell, yeast has become the workhorse of molecular genetics.

"What Lee did 25 years ago was essentially provide us with a list of all the important genes involved in controlling cell proliferation. This has proven to be invaluable in interpreting and using today's gene-sequence data. Second, Lee provided a logical framework to understand how these genes cooperate and work together to control cell division. Thus, he was not merely a cataloger of genes, but he also was able to explain how they worked," notes colleague James Roberts, MD, Ph.D., a Howard Hughes Medical Institute investigator and researcher at the Fred Hutchinson Cancer Research Center.

Hartwell identified more than one hundred genes involved in cell cycle control, known as CDC-genes (cell division cycle genes). His studies of the sensitivity of yeast cells to irradiation formed the basis for the concept of checkpoint, i.e. that the cell cycle is arrested when DNA is damaged. This allows the DNA to repair itself before the cell continues to the next phase of the cycle. These findings led to important insights into how cancer cells develop.

Using a different type of yeast, Schizzosaccharomyces pombe, British researcher Dr. Paul Nurse discovered identified, one of the key regulators of the cell cycle, CDK (cyclin dependent kinase). His work demonstrated that CDK controls the the cell cycle via the phosphorylation of other proteins.

Another British researcher, Dr. Timothy Hunt, used the Arbacia sea urchin as a model system to uncover the existence of cyclin molecules. These proteins are formed and degraded during each cell cycle. The levels of these proteins vary periodically during the cell cycle. The cyclins bind to the CDK molecules, regulating the activity of CDK activity, selecting the proteins to be phosphorylated.

Taken together, the work of the three biologists went a long way to explaining the basic molecular mechanisms involved in the regulation of the cell cycle. This research in turn opened the way to a better understanding of the chromosomal aberrations that result from defects in cell cycle control, resulting in cancer cells. Cancer researchers now know that genes for CDK-molecules and cyclins can function as oncogenes. In a different setting, CDK-molecules and cyclins collaborate with the products of tumor suppressor genes during the cell cycle. New cancer diagnostic tools based on this research are now entering the clinic. Clinical studies are also now getting underway using drugs that have been designed to inhibit CDK-molecules as a potential treatment for cancer.


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