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10.3C: Regulator Molecules of the Cell Cycle

  • Page ID
    13241
  • The cell cycle is controlled by regulator molecules that either promote the process or stop it from progressing.

    Learning Objectives

    • Differentiate among the molecules that regulate the cell cycle

    Key Points

    • Two groups of proteins, cyclins and cyclin-dependent kinases (Cdks), are responsible for promoting the cell cycle.
    • Cyclins regulate the cell cycle only when they are bound to Cdks; to be fully active, the Cdk/cyclin complex must be phosphorylated, which allows it to phosphorylate other proteins that advance the cell cycle.
    • Negative regulator molecules (Rb, p53, and p21) act primarily at the G1 checkpoint and prevent the cell from moving forward to division until damaged DNA is repaired.
    • p53 halts the cell cycle and recruits enzymes to repair damaged DNA; if DNA cannot be repaired, p53 triggers apoptosis to prevent duplication.
    • Production of p21 is triggered by p53; p21 halts the cycle by binding to and inhibiting the activity of the Cdk/cyclin complex.
    • Dephosphorylated Rb binds to E2F, which halts the cell cycle; when the cell grows, Rb is phosphorylated and releases E2F, which advances the cell cycle.

    Key Terms

    • cyclin: any of a group of proteins that regulates the cell cycle by forming a complex with kinases
    • cyclin-dependent kinase: (CDK) a member of a family of protein kinases first discovered for its role in regulating the cell cycle through phosphorylation
    • retinoblastoma protein: (Rb) a group of tumor-suppressor proteins that regulates the cell cycle by monitoring cell size

    Regulator Molecules of the Cell Cycle

    In addition to the internally controlled checkpoints, there are two groups of intracellular molecules that regulate the cell cycle. These regulatory molecules either promote progress of the cell to the next phase (positive regulation) or halt the cycle (negative regulation). Regulator molecules may act individually or they can influence the activity or production of other regulatory proteins. Therefore, the failure of a single regulator may have almost no effect on the cell cycle, especially if more than one mechanism controls the same event. 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.

    Positive Regulation of the Cell Cycle

    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. 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.

    image

    Cyclin Concentrations at Checkpoints: 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.

    Cyclins regulate the cell cycle only when they are tightly bound to Cdks. To be fully active, the Cdk/cyclin complex must also be phosphorylated in specific locations. 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 levels of Cdk proteins are relatively stable throughout the cell cycle; however, the concentrations of cyclin fluctuate and determine when Cdk/cyclin complexes form. The different cyclins and Cdks bind at specific points in the cell cycle and thus regulate different checkpoints.

    image

    Activation of Cdks: Cyclin-dependent kinases (Cdks) are protein kinases that, when fully activated, can phosphorylate and 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.

    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 being monitored is completed.

    Negative Regulation of the Cell Cycle

    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 p21. Retinoblastoma proteins are a group of tumor-suppressor proteins common in many cells. 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 G1 checkpoint. p53 is a multi-functional protein that has a major impact on the cell’s commitment to division; it acts when there is damaged DNA in cells that are undergoing the preparatory processes during G1. If damaged DNA is detected, p53 halts the cell cycle and recruits enzymes to repair the DNA. If the DNA cannot be repaired, p53 can trigger apoptosis (cell suicide) to prevent the duplication of damaged chromosomes. As p53 levels rise, the production of p21 is triggered. p21 enforces the halt in the cycle dictated by p53 by binding to and inhibiting the activity of the Cdk/cyclin complexes. 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. Rb monitors cell size. In the active, dephosphorylated state, Rb binds to proteins called transcription factors, most commonly to E2F. Transcription factors “turn on” specific genes, allowing the production of proteins encoded by that gene. When Rb is bound to E2F, production of proteins necessary for the G1/S transition is blocked. As the cell increases in size, Rb is slowly phosphorylated until it becomes inactivated. Rb releases E2F, which can now turn on the gene that produces the transition protein and this particular block is removed. For the cell to move past each of the checkpoints, all positive regulators must be “turned on” and all negative regulators must be “turned off.”

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    Function of the Rb Regulator Molecule: Rb halts the cell cycle by binding E2F. Rb releases its hold on E2F in response to cell growth to advance the cell cycle.

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