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Chapter 7

BIOL 200 Chapter 7: BIOL 200 ONLINE NOTES CH7.2

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BIOL 200
Robin Young

Topic 7.2 - CDK - Cyclin Regulation The last topic introduced the idea that the cell is broken down into several stages, in which particular events must occur. Like all things in bioloy, there was a time when the details of the cell cycle stages were not known to scientists. The first experiments that showed that there was something controlling the progression of the cell cycle involved injection of cytoplasm into the very large cells of frog (Xenopus laevis) oocytes. In each case, the cytoplasm from one oocyte that was at one stage of the cell cycle, was injected into another oocyte, as shown in the image below. These results show that:  The active agent is in the cytoplasm of the cell  Control of DNA synthesis and mitosis is positive. That is, that the active agent turns on the process in the recipient cell which is capable to respond but had not yet gotten around to initiating the process itself.  That cells can be advanced into the next stage by appropriate factors. Based on experiments such as these, scientists identified that there was some cytoplasmic 'factor' that helped to promote the cell's progression into mitosis. As a result, they called this the Mitosis Promoting Factor (MPF). Since the discovery of MPF, a great deal of work has been done to understand more specifically what was regulating the progression of the cell into mitosis. We now know that the active agent is a protein called Cyclin-Dependant Kinase (CDK) (Important Note: a kinase is a protein that is capable of adding phosphate groups to other proteins). It regulates the activity of a large number of other proteins that are required for cell cycle progression by phosphorylating them. Proteins can be phosphorylated by adding phosphate groups to specific amin acid side chains that bear hydroxyl groups (serine, threonine, tyrosine). Phosphorylation can result in big changes in tertiary structure of proteins. What happens if a highly charged group is added to or removed from a protein? We have already seen one example of phosphorylation modifying the function of a protein... can you remember where? (Hint: Topic 3.1 and then again in topic 6.1) In addition to CDK, MPF also contains second protein that interacts with CDK, known as cyclin. Cyclin binds to cyclin-dependant kinase, and acts as a regulatory unit; CDK can ONLY perform its function as a kinase when cyclin is bound. If cylcin is removed from CDK, then CDK is inactivated. This is also the source of its name... cyclin-dependant kinase. These two proteins combine to produce a single enzyme, the cyclin-CDK complex. While CDK concentrations remain constant throughout the cell cycle, cyclin levels build up during the cell cycle and the crash to zero at the end of mitosis (How might that happen?). Figure 18-5 (both editions) Cyclin concentration vs. CDK-cyclin enzyme activity. CDK has is ONLY functional when it is bound to cyclin, thus the degradation of cyclin at the end of mitosis effectively shuts off CDK activity and allows the cell to move out of M-phase and into G . 1 In addition to this, the CDK-cyclin complex can be phosphorylated in several places (by other kinases), which will also have a role in activating/ deactivating the complex. Cyclin-CDK's are very tightly controlled as the consequences of a cell moving into the next stage of the cell cycle before its ready could be fatal. The activity of the cyclin-CDK complex is controlled by two independent processes (shown in the figure below):  The binding/proteolysis of cyclin, and  The phosphorylation of CDK MPF contains the activated cyclin-CDK complex that promotes entry into mitosis, which we call M-CDK- cyclin. It is important to remember that there are several cyclins and CDKs involved in regulating the cell cycle at several stages, as shown in the table below. It is these complexes that control the checkpoints that we discussed in Topic 8.1. In this course we will focus primarily on those involved in entry into M-phase, with some discussion of S-phase cyclin-CDKs as well. Figure 18-8 (3rd ed. 18-10). Relative concentrations of S- and M- cyclins throughout the cell cycle. Phosphorylation controls CDK activity Phosphorylation of specific amino acid residues (usually serines, threonines or tyrosines) can be used to activate or inhibit protein activity. In the case of CDK, it is possible that BOTH activating AND inhibitory phosphates are added and/ or removed, depending on the cyclin-CDK complex that we are discussing. The specifics of all of the ways that cyclin-CDK gets phosphorylated is beyond the scope of this course, other than knowing about the first inhibitory phosphate, as described below: The activation of a cyclin-CDK complex happens as follows: 1. Cyclin levels begin to build up well before the checkpoint. For example, M-cyclin synthesis begins at the end of S-phase and builds up until the onset of mitosis. 2. CDK combines with cyclin. The interaction between the subunits changes the configuration of the active site of the CDK and makes it possible for the enzyme to become active. Interaction with cyclin is necessary, but not sufficient for CDK enzyme activity. 3. Inhibitory phosphorylation. The phosphates are added by specific protein kinases onto specific tyrosine residues in the CDK primary sequence. Its worthwhile to note that this may not be the only phosphorylation that takes place. Some CDKs also need activating phosphates added. Some of the images in your textbook show this as well. Here is a more detailed figure on events in budding yeast. 4. When the cell is prepared to pass the checkpoint, removal of the inhibiting phosphate occurs by action of a specific phosphatase. At this point CDK-cyclin becomes enzymatically active. M-CDK controls entry into mitosis, and re-entry into G1 In yeast, the two key regulator proteins for M-cyclin-CDK activation are wee1 and cdc25. The antagonistic relationship of wee1 and cdc25 was discovered using genetic experiments in which the dosage of the genes was exper
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