Control of the Cell Cycle

Learning Objectives

By the end of this section, you will be able to:

  • Understand how the cell cycle is controlled by mechanisms both internal and external to the cell
  • Explain how the three internal control checkpoints occur at the end of G1, at the G2/M transition, and during metaphase
  • Describe the molecules that control the cell cycle through positive and negative regulation

The length of the cell cycle is highly variable, even within the cells of a single organism. In humans, the frequency of cell turnover ranges from a few hours, to an average of two to five days, and to an entire human lifetime spent in G0 by specialized cells.  Variation occurs in the time a cell spends in each phase.   When fast-dividing mammalian cells are grown in culture, the length of the cycle is about 24 hours. In rapidly dividing human cells with a 24-hour cell cycle, the G1 phase lasts approximately nine hours, the S phase lasts 10 hours, the G2 phase lasts about four hours.  Mitosis lasts approximately one-half hour.  The timing of events in the cell cycle is controlled by external and internal mechanisms.

Regulation of the Cell Cycle by External Events

As replication begins, the initiation and inhibition of cell division is triggered by external events.  An event may be as simple as the death of a nearby cell or as complex as the release of hormones.   A lack HGH, a growth hormone, can inhibit cell division, resulting in dwarfism, Too much HGH can be released resulting in gigantism.  Another factor that can initiate cell division is the cell size.  As a cell grows, it becomes inefficient due to its decreasing surface-to-volume ratio. The solution to this problem would be for cell division to occur.

Regulation at Internal Checkpoints

It is essential that the daughter cells be exact duplicates of the parent cell. Mistakes in the duplication or distribution of the chromosomes lead to mutations that may be passed forward during further cell divisions.  To prevent an abnormal cell from continuing, there are internal control mechanisms that operate at three main cell cycle checkpoints. A checkpoint is one of several points in the eukaryotic cell cycle at which the progression to the next stage can be halted until conditions are favorable. These checkpoints occur near the end of G1, at the G2/M transition, and during metaphase (Figure 1).

This illustration shows the three major checkpoints of the cell cycle: G_{1}, G_{2}, and M.

Figure 1. The cell cycle is controlled at three checkpoints. The integrity of the DNA is assessed at the G1 checkpoint. Proper chromosome duplication is assessed at the G2 checkpoint. Attachment of each kinetochore to a spindle fiber is assessed at the M checkpoint.

The G1 Checkpoint

The G1 checkpoint determines whether all conditions are favorable for cell division to proceed. The G1 checkpoint is a point at which the cell irreversibly commits to the cell division.  External influences play a large role in carrying the cell past the G1 checkpoint. In addition to adequate protein reserves and cell size, there is a check for genomic DNA damage at the G1 checkpoint. A cell that does not meet all the requirements will not be allowed to progress into the S phase. The cell can halt the cycle and attempt to remedy the problem or the cell can advance into G0 to await further signals should conditions improve.

The G2 Checkpoint

The G2 checkpoint bars entry into the mitotic phase.  As at the G1 checkpoint, protein reserves and cell size are assessed. However, the most important role of the G2 checkpoint is to ensure that all of the chromosomes have been replicated without damage.  If the checkpoint mechanisms detect problems with the DNA, the cell cycle is halted.  The cell attempts to either complete DNA replication or repair the damaged DNA.

The M Checkpoint

The M checkpoint occurs near the end of the metaphase stage of karyokinesis. The M checkpoint, also known as the spindle checkpoint,  determines whether all the sister chromatids are correctly attached to the spindle microtubules. Because the separation of the sister chromatids during anaphase is an irreversible step, the cycle will not proceed until the kinetochores of each pair of sister chromatids are firmly anchored to at least two spindle fibers arising from opposite poles of the cell.

Section Summary

Each step of the cell cycle is monitored by internal controls called checkpoints. There are three major checkpoints in the cell cycle: one near the end of G1, a second at the G2/M transition, and the third during metaphase.

Additional Self Check Questions

1. Rb and other proteins that negatively regulate the cell cycle are sometimes called tumor suppressors. Why do you think the name tumor suppressor might be an appropriate for these proteins?

2. Describe the general conditions that must be met at each of the three main cell cycle checkpoints.

3. Explain the roles of the positive cell cycle regulators compared to the negative regulators.

4. What steps are necessary for Cdk to become fully active?

5. Rb is a negative regulator that blocks the cell cycle at the G1 checkpoint until the cell achieves a requisite size. What molecular mechanism does Rb employ to halt the cell cycle?

Answers

1.  Rb and other negative regulatory proteins control cell division and therefore prevent the formation of tumors. Mutations that prevent these proteins from carrying out their function can result in cancer.

2. The G1 checkpoint monitors adequate cell growth, the state of the genomic DNA, adequate stores of energy, and materials for S phase. At the G2 checkpoint, DNA is checked to ensure that all chromosomes were duplicated and that there are no mistakes in newly synthesized DNA. Additionally, cell size and energy reserves are evaluated. The M checkpoint confirms the correct attachment of the mitotic spindle fibers to the kinetochores.

3. Positive cell regulators such as cyclin and Cdk perform tasks that advance the cell cycle to the next stage. Negative regulators such as Rb, p53, and p21 block the progression of the cell cycle until certain events have occurred.

4. Cdk must bind to a cyclin, and it must be phosphorylated in the correct position to become fully active.

5. Rb is active when it is dephosphorylated. In this state, Rb binds to E2F, which is a transcription factor required for the transcription and eventual translation of molecules required for the G1/S transition. E2F cannot transcribe certain genes when it is bound to Rb. As the cell increases in size, Rb becomes phosphorylated, inactivated, and releases E2F. E2F can then promote the transcription of the genes it controls, and the transition proteins will be produced.

Glossary

cell cycle checkpoint:  mechanism that monitors the preparedness of a eukaryotic cell to advance through the various cell cycle stages

cyclin:  one of a group of proteins that act in conjunction with cyclin-dependent kinases to help regulate the cell cycle by phosphorylating key proteins; the concentrations of cyclins fluctuate throughout the cell cycle

cyclin-dependent kinase:  one of a group of protein kinases that helps to regulate the cell cycle when bound to cyclin; it functions to phosphorylate other proteins that are either activated or inactivated by phosphorylation

p21:  cell cycle regulatory protein that inhibits the cell cycle; its levels are controlled by p53

p53:  cell cycle regulatory protein that regulates cell growth and monitors DNA damage; it halts the progression of the cell cycle in cases of DNA damage and may induce apoptosis

retinoblastoma protein (Rb):  regulatory molecule that exhibits negative effects on the cell cycle by interacting with a transcription factor (E2F)