Conversely, the effect of a deficient or non-functioning regulator can be wide-ranging and possibly fatal to the cell if multiple processes are affected. Two groups of proteins, called cyclins and cyclin-dependent kinases Cdks , are responsible for the progress of the cell through the various checkpoints.
The levels of the four cyclin proteins fluctuate throughout the cell cycle in a predictable pattern Figure 2. Increases in the concentration of cyclin proteins are triggered by both external and internal signals. After the cell moves to the next stage of the cell cycle, the cyclins that were active in the previous stage are degraded.
Figure 2. The concentrations of cyclin proteins change throughout the cell cycle. There is a direct correlation between cyclin accumulation and the three major cell cycle checkpoints. Also note the sharp decline of cyclin levels following each checkpoint the transition between phases of the cell cycle , as cyclin is degraded by cytoplasmic enzymes.
Figure 3. Cyclin-dependent kinases Cdks are protein kinases that, when fully activated, can phosphorylate and thus activate other proteins that advance the cell cycle past a checkpoint.
To become fully activated, a Cdk must bind to a cyclin protein and then be phosphorylated by another kinase. Cyclins regulate the cell cycle only when they are tightly bound to Cdks. Like all kinases, Cdks are enzymes kinases that phosphorylate other proteins. Phosphorylation activates the protein by changing its shape. The proteins phosphorylated by Cdks are involved in advancing the cell to the next phase.
The different cyclins and Cdks bind at specific points in the cell cycle and thus regulate different checkpoints. Although the cyclins are the main regulatory molecules that determine the forward momentum of the cell cycle, there are several other mechanisms that fine-tune the progress of the cycle with negative, rather than positive, effects.
These mechanisms essentially block the progression of the cell cycle until problematic conditions are resolved. Molecules that prevent the full activation of Cdks are called Cdk inhibitors.
Many of these inhibitor molecules directly or indirectly monitor a particular cell cycle event. The block placed on Cdks by inhibitor molecules will not be removed until the specific event that the inhibitor monitors is completed. The second group of cell cycle regulatory molecules are negative regulators.
Negative regulators halt the cell cycle. Remember that in positive regulation, active molecules cause the cycle to progress. The best understood negative regulatory molecules are retinoblastoma protein Rb , p53, and p Retinoblastoma proteins are a group of tumor-suppressor proteins common in many cells.
The 53 and 21 designations refer to the functional molecular masses of the proteins p in kilodaltons. Much of what is known about cell cycle regulation comes from research conducted with cells that have lost regulatory control. All three of these regulatory proteins were discovered to be damaged or non-functional in cells that had begun to replicate uncontrollably became cancerous.
In each case, the main cause of the unchecked progress through the cell cycle was a faulty copy of the regulatory protein. Rb, p53, and p21 act primarily at the G 1 checkpoint. If the DNA cannot be repaired, p53 can trigger apoptosis, or cell suicide, to prevent the duplication of damaged chromosomes. As p53 levels rise, the production of p21 is triggered.
As a cell is exposed to more stress, higher levels of p53 and p21 accumulate, making it less likely that the cell will move into the S phase. Rb exerts its regulatory influence on other positive regulator proteins. Chiefly, Rb monitors cell size. In the active, dephosphorylated state, Rb binds to proteins called transcription factors, most commonly, E2F Figure 4. Here, we will discuss more specifically the proteins that interact to regulate the cell cycle.
The "checkpoints" that we described earlier are established by proteins that use cues from the cell's environment to trigger the entry to and exit from the distinct phases of the cell cycle. We will discuss two main families of proteins involved in this process—cyclin-dependent protein kinases Cdks and cyclins.
A Cdks is an enzyme that adds negatively charged phosphate groups to other molecules in a process called phosphorylation. Through phosphorylation, Cdks signal the cell that it is ready to pass into the next stage of the cell cycle. As their name suggests, Cyclin-Dependent Protein Kinases are dependent on cyclins, another class of regulatory proteins. Cyclins bind to Cdks, activating the Cdks to phosphorylate other molecules.
Cyclins are named such because they undergo a constant cycle of synthesis and degradation during cell division. When cyclins are synthesized, they act as an activating protein and bind to Cdks forming a cyclin-Cdk complex. This complex then acts as a signal to the cell to pass to the next cell cycle phase.
Eventually, the cyclin degrades, deactivating the Cdk, thus signaling exit from a particular phase. There are two classes of cyclins: mitotic cyclins and G1 cyclins. Figure 1: The sequence of eukaryotic cell cycle phases Between each arrow, the cell passes through a particular cell cycle checkpoint. Figure Detail. Of the many proteins involved in cell cycle control, cyclin-dependent kinases CDKs are among the most important.
CDKs are a family of multifunctional enzymes that can modify various protein substrates involved in cell cycle progression. Specifically, CDKs phosphorylate their substrates by transferring phosphate groups from ATP to specific stretches of amino acids in the substrates.
Different types of eukaryotic cells contain different types and numbers of CDKs. For example, yeast have only a single CDK, whereas vertebrates have four different ones. All eukaryotes have multiple cyclins, each of which acts during a specific stage of the cell cycle. All cyclins are named according to the stage at which they assemble with CDKs. All CDKs exist in similar amounts throughout the entire cell cycle. In contrast, cyclin manufacture and breakdown varies by stage — with cell cycle progression dependent on the synthesis of new cyclin molecules.
Cyclin degradation is equally important for progression through the cell cycle. Specific enzymes break down cyclins at defined times in the cell cycle. When cyclin levels decrease, the corresponding CDKs become inactive. Cell cycle arrest can occur if cyclins fail to degrade. Figure 2: The classical and minimal models of cell cycle control Where and when do cyclins act on the cell cycle?
A Cycling cells undergo three major transitions during their cell cycle. The beginning of S phase is marked by the onset of DNA replication, the start of mitosis M is accompanied by breakdown of the nuclear envelope and chromosome condensation, whereas segregation of the sister chromatids marks the metaphase-to-anaphase transition. Cyclin-dependent kinases CDKs trigger the transition from G1 to S phase and from G2 to M phase by phosphorylating distinct sets of substrates.
Thick lines represent the preferred pairing for each kinase. D Based on the results of cyclin and CDK-knockout studies, scientists have constructed a new threshold model of cell cycle control. The differences between interphase and mitotic CDKs are not necessarily due to substrate specificity, but are more likely a result of different localization and a higher activity threshold for mitosis than interphase.
Cyclin-dependent kinases and cell-cycle transitions: does one fit all? Nature Reviews Molecular Cell Biology 9, All rights reserved. This page appears in the following eBook.
0コメント