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The Oncologist, Vol. 9, No. 5, 592-593, September 2004; doi:10.1634/theoncologist.9-5-592
© 2004 AlphaMed Press

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Fundamentals of Cancer Medicine

The Molecular Perspective: Cyclins

David S. Goodsell

Correspondence: David S. Goodsell, Ph.D., Associate Professor, The Scripps Research Institute, Department of Molecular Biology, 10550 North Torrey Pines Road, La Jolla, California 92037, USA. Telephone: 858-784-2839; Fax: 858-784-2860; e-mail: goodsell{at}scripps.edu Website: http://www.scripps.edu/pub/goodsell


   LEARNING OBJECTIVE
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 Learning Objective
Further Reading
 
After completing this course, the reader will be able to:

  • Describe the role of cyclins and cyclin-dependent kinases in cancer.

Access and take the CME test online and receive 1 hour of AMA PRA category 1 credit at CME.TheOncologist.com

The life of a cell is cyclical. Most of a human cell’s life is spent in performing its particular function, whether it be contraction, digestion, transportation, regulation, or cognition. But for many cells—in the skin, in the blood, and in other actively growing places around the body—there comes a time when they switch gears and decide to divide. Then, everything changes. Replication machinery is mobilized to duplicate the DNA, forming a single identical copy. The DNA is condensed and packaged into compact chromosomes. The two-layer nuclear envelope is dissolved, and an engine of microtubules separates the two sets of chromosomes. Finally, the cell splits in two. Each daughter cell restores its DNA to activity, rebuilds a fresh nuclear infrastructure, and settles back into normal life.

This massively disruptive process must be choreographed to perfection, ensuring that each task occurs at the proper time and in the proper order. This is the job of the cyclin proteins. Inside cells, the levels of cyclins oscillate, marking time like a clock to keep the cell in step. Several cyclins are used in our cells, including one to initiate DNA synthesis and one to start mitosis. When the amount of each cyclin increases to a threshold level, the process is triggered. Then, after the task is finished, the cyclins are rapidly degraded, making way for the next task. The slow rise and fall of each cyclin in turn marches the cell through the division cycle.

When the amount of each cyclin reaches the proper level, many different cellular processes are initiated. The cyclin protein itself does not directly activate all these molecular machines; instead, cyclins act through cyclin-dependent kinase enzymes. As shown in Figure 1Go, cyclin activates these enzymes by binding to one side and opening up the active site. Then, the activated kinases add phosphate groups to proteins throughout the cell, mobilizing all the machinery needed for DNA synthesis, or chromosome segregation, or whatever task is specified by the particular cyclin.



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  		Figure 1. Cyclin and cyclin-dependent kinase. The kinase shown at left has a deep groove that binds ATP, shown in green. ATP provides the phosphate that is transferred during the phosphorylation reaction. A loop of the kinase, shown in pink, folds up and blocks the active site when the enzyme is free. When cyclin (shown in blue on the right) binds, this loop is pried away, opening the active site and allowing the complex of cyclin and kinase to add phosphate groups to proteins in the cell-division machinery. The kinase enzyme itself is also activated by phosphorylation: a phosphate group (shown here in bright red and yellow) is added to the kinase loop to bring it into its fully active form. Coordinates were taken from entries 1hck and 1jst at the Protein Data Bank (http://www.pdb.org).

 
As you might guess, the process is not quite that simple. Our cells add a complex collection of activators and inhibitors to tune the orderly progression of the cell cycle. Some of these proteins block cyclins (Fig. 2Go) or lead to their breakdown, postponing cell division until everything is in its proper place. Others relay growth signals from neighboring cells and enhance the action of cyclins, promoting cell division when the local conditions are right.



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  		Figure 2. Cyclin-dependent kinase inhibitor. One of the natural modulators of the cyclin system is shown here in green. The small protein chain embraces both the cyclin and the kinase, insinuating itself into the active site and blocking the action of the enzyme. Coordinates were taken from entry 1jsu at the Protein Data Bank.

 
Cancer cells often carry mutations that modify these controls, blocking check points and enhancing the push toward division, leading to abnormal proliferation. Researchers are currently testing therapies that attack this unchecked growth at the level of cyclin action. Inhibitors have been developed to block the action of the cyclin-dependent kinases. These inhibitors bind in place of ATP, stopping the phosphorylation action of the enzyme, ultimately freezing the cells in the nondividing state or triggering the cell to commit suicide through apoptosis.


   FURTHER READING
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 Learning Objective
 Further Reading
 

    Morgan DO. Cyclin-dependent kinases: engines, clocks, and microprocessors. Annu Rev Cell Dev Biol 1997;13:261–291.[CrossRef][Medline]

    Pavletich NP. Mechanisms of cyclin-dependent kinase regulation: structures of Cdks, their cyclin activators, and Cip and INK4 inhibitors. J Mol Biol 1999;287:821–828.[CrossRef][Medline]

    Knockaert M, Greengard P, Meijer L. Pharmacological inhibitors of cyclin-dependent kinases. Trends Pharmacol Sci 2002;23:417–425.[CrossRef][Medline]

Received August 2, 2004; accepted for publication August 2, 2004.





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