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REGULATORS OF THE CELL CYCLE
Discovery of cyclins, cyclin-dependent kinases earns medicine Nobel Prize
Two geneticists and a biochemist will share this year's Nobel Prize in Physiology or Medicine for "discovering the molecular mechanisms that regulate the cell cycle" in higher organisms.
Leland H. Hartwell, 61, president and director of the Fred Hutchinson Cancer Research Center, Seattle, and professor of genetics at the University of Washington, will share the approximately $950,000 prize with biochemist R. Timothy Hunt, 58, and geneticist Sir Paul M. Nurse, 52. Nurse is director-general of Britain's Imperial Cancer Research Fund, London, where Hunt is a principal scientist.
Hartwell was the first to discover that the products of specific genes are responsible for controlling the cycle of growth and division in cells. In experiments in yeast, he identified more than 100 genes specifically involved in cell-cycle control. By studying how yeast cells respond to damage caused by radiation, Hartwell developed the concept of checkpoints where cells pause, if need be, in the cell cycle to repair damage. It's now understood that these checkpoints are defective in most cancer cells. Hartwell also identified the specific yeast gene that controls passage through the first checkpoint in the cell cycle.
Nurse, using a different yeast strain, also identified many of the genes that regulate the cell cycle. In particular, he identified the gene that controls passage into the part of the cell cycle known as mitosis, when chromosomes separate. He later showed that his gene and Hartwell's were the same, establishing that this gene's product regulates different phases of the cell cycle. Nurse also found the corresponding gene in humans. The gene encodes a protein that in humans is called cyclin-dependent kinase 1 (CDK-1).
Hunt, studying sea urchins, identified a protein he named cyclin because its level rises and falls during the cell cycle. Cyclins, it is now known, bind to CDKs to activate them. The amount of CDK molecules remains constant in a cell, but the molecules' activity varies because of the regulatory function of the cyclins.
The prize "is highly appropriate, both in terms of the field and the people selected," says David O. Morgan, professor of physiology at UC San Francisco. "The process of cell division is an immensely important aspect of biology, and the work of these three people in the 1970s and '80s broke the field wide open."
The machinery discovered by these researchers is the same in humans, yeast, sea urchins, frogs, and even plants, notes Helen M. Piwnica-Worms, professor of cell biology, physiology, and internal medicine at Washington University School of Medicine, St. Louis. "The chemistry/biology interface in this area is exploding as the pharmaceutical industry seeks to develop drugs that target the cell cycle machinery or regulators of this machinery to kill human cancer cells."
"It's a fantastic choice," says Kevan Shokat, associate professor of cellular and molecular pharmacology at UCSF. The work being honored "provides a lot of what I call the substrates for chemical biology. It tells us all the names and some of the functions of the proteins that control the cell cycle and how chemical biologists might think about correcting some of the problem events in cancer cells."
"For Hartwell and Nurse, it was just a question of when, not if," they would win the Nobel Prize, says Harvard cell biologist Timothy J. Mitchison, codirector of the Harvard Institute of Chemistry & Cell Biology. Choosing the third winner may have been harder, he suggests. "Since cell cycle regulation was--and is being--solved by a confluence of genetic and biochemical approaches, we all hoped a biochemist would be in on this prize," Mitchison says.
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