FIG. 11.15

How is progression through the cell cycle controlled?

BACKGROUND The cell cycle is characterized by cyclical changes in many components of the cell: Chromosomes condense and decondense, the mitotic spindle forms and breaks down, the nuclear envelope breaks down and re-forms. How these regular and cyclical changes are controlled is the subject of active research. First, clues came from studies in yeast in which mutations in certain genes blocked progression through the cell cycle, suggesting that these genes encode proteins that play a role in cell cycle progression. Additional clues came from studies in embryos of the sea urchin Arbacia punctulata. These embryos are large and divide rapidly by mitosis, making them a good model system for the study of the control of cell division. In the early 1980s, it was known that inhibition of protein synthesis blocks key steps of cell division in sea urchins. It was also known that an enzyme called MPF, or M-phase promotion factor, is important for the transition from G₂ to M phase.

EXPERIMENT To better understand events in the cell cycle, English biochemist Tim Hunt and colleagues measured protein levels in sea urchin embryos as they divide rapidly by mitosis. He added radioactive methionine (an amino acid) to eggs, which became incorporated into any newly synthesized proteins. The eggs were then fertilized and allowed to develop. Samples of the rapidly dividing embryos were taken every 10 minutes and run on a gel to visualize the levels of different proteins.

RESULTS Most protein bands became darker as cell division proceeded, indicating more and more protein synthesis. However, the level of one protein band oscillated, increasing in intensity and then decreasing with each cell cycle, as shown in the graph.

CONCLUSION Hunt and colleagues called this new protein “cyclin.” Although they did not know its function, its fluctuating level suggested it might play a role in the control of the cell cycle. However, more work was needed to figure out if cyclins actually cause progression through the cell cycle or whether their levels oscillate in response to progression through the cell cycle.

FOLLOW-UP WORK Hunt and colleagues found a similar rise and fall in the levels of certain proteins in the sea urchin Lytechinus pictus and surf clam Spisula solidissima. MPF was found to consist of a cyclin protein and a cyclin-dependent kinase that play a key role in the G₂–M transition. In other words, cyclins do in fact control progression through the cell cycle by their interactions with cyclin-dependent kinases. Hunt shared the Nobel Prize in Physiology or Medicine in 2001 for his work on cyclins.

SOURCE T. Evans et al. 1983. “Cyclin: A Protein Specified by Maternal mRNA in Sea Urchin Eggs That Is Destroyed at Each Cleavage Division.” Cell 33:389–396.