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Volume 12, No. 1, Spring 02 | Return to Table of Contents
Cells, Clams,and Cancer: The MBL Cyclin Story
From the moment of conception, our cells are driven to divide. A single-celled embryo becomes two cells; those cells then divide to become four. Our cells divide and divide and divide, eventually creating a 100,000 billion celled being known as human. As we grow from infancy to childhood to adulthood, our cells are constantly going through the complex biochemical process of duplicating themselves. It’s a cascade of events that’s been going on within cells for millions of years—one that’s regulated, it turns out, by a few key proteins.
Scientists had long suspected that certain proteins played a role in cell division. There had to be “periodic proteins” that signaled the cell to take one step, then the next, on its way to duplicating itself. It wasn’t until Tim Hunt, Joan Ruderman (Harvard Medical School), and her student Eric Rosenthal conducted an “elegant experiment” more than 20 years ago in the teaching labs of the Embryology course that light began being shed on the subject.
While studying the synthesis of proteins in fertilized eggs of surf clams, Rosenthal noticed that the activity of certain proteins appeared to be “turned on” after the eggs were fertilized. It was an interesting observation that “made sense,” says Hunt.
“Changing an egg into an embryo presumably needs new proteins,” writes Hunt. “But we had no idea what the new proteins were.” Or what role they really played inside the cell. Three years and many, sometimes frustrating, experiments later, Hunt would find out.
Back in Woods Hole, this time using the sea urchin as a model and working with students in the 1982 Physiology course, Hunt decided to do “a simple experiment, purely out of curiosity.” The result was “a revelation,”
he recalls. And “completely unexpected.” He had discovered a protein that appeared at a certain point during cell division, but which disappeared entirely just as the cell began
to split.
Hunt knew at that moment that he’d made an important discovery. He named the protein cyclin, and quickly went about writing up the results.
This seminal paper was published in the journal Cell in 1983.
“That paper insightfully predicted that cyclin might have a role in cell cycle control,” says Ruderman. It was “an idea that was subsequently validated beyond anyone’s wildest expectations.” Eighteen years after the Cell paper was published, Hunt was awarded the Nobel Prize for the ground-breaking discovery.
Ruderman made a significant contribution to the field as well during the summer of 1982 by cloning the first cyclin gene from surf clam eggs. This accomplishment was a critical next chapter in the MBL cyclin story. It enabled investigators to later “demonstrate directly that cyclins do indeed regulate the cell cycle and to discover how they work at the molecular level,” says Ruderman.
During subsequent summers at the MBL, Ruderman and her colleagues continued studying cyclin and surf clam eggs. In 1986, they published the first molecular evidence that cyclins do help regulate cell division cycle. They showed that when cloned cyclin was injected into non-dividing cells, it made those cells divide. By 1989 they had shown definitively how cyclin interacts with, and activates other, key enzymes during the cell cycle.
By the late 1980s, Ruderman had also developed a key system for studying the cell cycle and the degradation of cyclin in a test tube.
“Many important regulators of the cell cycle are degraded in a programmed fashion, which allows the cell cycle to progress,” explains MBL summer investigator Avram Hershko of the Technion-Israel Institute of Technology. Hershko was drawn to the MBL more than 10 years ago when he became interested in learning more about the role a certain protein, known as ubiquitin, plays in the cell cycle. Ruderman’s in vitro system was exactly what Hershko needed to test his theories.
Working with Ruderman and Robert Palazzo (University of Kansas), Hershko showed that a specific ubiquitin ligating complex “targets cyclin B for degradation at the end of mitosis”—the final phase of cell division. Hershko’s work on the ubiquitin system of regulated protein degradation won him the coveted Albert Lasker Award for Basic Medical Research in 2000.
Hershko, Palazzo, and Ruderman return to the MBL each summer as members of the “clam cluster” in the Whitman Building. They and their colleagues George Langford, Robert Goldman, Roger Sloboda, Conly Rieder, and others use the surf clam as a model for studying a variety of complex processes within the cell.
In recent years, Ruderman’s work has resulted in the identification of a newly cloned human oncogene as a member of the cyclin family. Hershko continues his studies of the ubiquitin ligating complex in hopes of learning more about the regulation of cell division in general and cancer in particular. And Palazzo has developed methods for isolating and analyzing a cell organelle that plays a key role in cell replication—the centrosome.
Tim Hunt will return to Woods Hole again this summer. He’ll give the final presentation in the 2002 Friday Evening Lecture series on August 16th. |
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