Control of the Cell Cycle
Inquire: Controlled and Uncontrolled Cell Cycle
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. Positive regulator molecules allow the cell cycle to advance to the next stage. Negative regulator molecules monitor cellular conditions and can halt the cycle until specific requirements are met.
Cancer is the result of unchecked cell division caused by a breakdown of the mechanisms that regulate the cell cycle. The loss of control begins with a change in the DNA sequence of a gene that codes for one of the regulatory molecules. Any disruption of the cell cycle can allow other mistakes to be passed on to the daughter cells. Each successive cell division will give rise to daughter cells with even more accumulated damage.
How is the cell cycle regulated?
Watch: Controlling the Cell Cycle
Read: Regulation of the Cell Cycle
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 in early embryonic development to an average of two to five days for epithelial (tissue that covers a surface) cells, and to an entire human lifetime spent in G0 (resting phase) by specialized cells, such as cortical neurons (nerve cells that make up the cortex of the brain) or cardiac muscle cells. There is also variation in the time that a cell spends in each phase of the cell cycle. 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 and one-half hours, and the M phase lasts approximately one half hour. In early embryos of fruit flies, the cell cycle is completed in about eight minutes. The timing of events in the cell cycle is controlled by mechanisms that are both internal and external to the cell.
Regulation of the Cell Cycle by External Events
Both the initiation and inhibition of cell division are triggered by events external to the cell when it is about to begin the replication process. An event may be as simple as the death of a nearby cell or as big as the release of growth-promoting hormones, such as human growth hormone (HGH). A lack of HGH can prevent cell division, resulting in dwarfism, whereas too much HGH can result in gigantism. Crowding of cells can also prevent cell division. Another factor that can initiate cell division is the size of the cell; as a cell grows, it becomes inefficient due to its decreasing surface-to-volume ratio. The solution to this problem is to divide.
Regulation at Internal Checkpoints
To prevent an infected cell from continuing to divide, internal control mechanisms operate at three main cell-cycle checkpoints. A checkpoint is one of several points in the eukaryotic cell cycle at which the progression of a cell to the next stage in the cycle can be stopped until conditions are favorable. These checkpoints occur near the end of G1, at the G2/M transition, and during metaphase.
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 commits to the cell division process. External influences, such as growth factors, play a large role in carrying the cell past the G1 checkpoint. In addition to adequate 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 problematic condition, or the cell can advance into G0 and wait for further signals when conditions improve.
The G2 Checkpoint
The G2 checkpoint stops entry into the mitotic phase if certain conditions are not met. The most important role of the G2 checkpoint is to ensure that all of the chromosomes have been replicated and that the replicated DNA is not damaged. If the checkpoint mechanisms detect problems with the DNA, the cell cycle is stopped, and 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 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 attached to at least two spindle fibers coming from opposite poles of the cell.
Regulator Molecules of the Cell Cycle
Two groups of intracellular molecules regulate the cell cycle. These regulatory molecules either promote progress (positive regulation) of the cell to the next phase or stop 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. However, 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 termed positive regulators. They 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 by cytoplasmic enzymes.
The second group of cell-cycle regulatory molecules are negative regulators, which stop 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 (p refers to protein), 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 (i.e., become cancerous). In each case, the main cause of the unchecked progress through the cell cycle was a faulty copy of the regulatory protein.
Reflect: Stages of Cancer
You may hear someone talking about the stages of cancer. Most cancers are categorized in stages one through four. Cancer that is small and contained in the organ it started in is stage one. A tumor that is larger than stage one but has not spread is stage two. When the cancer becomes even larger having spread to surrounding tissues and in the lymph nodes, this is stage three. Stage four is when cancer has spread to another organ, called metastatic cancer. Think of someone you know or have heard about who has been diagnosed with cancer.
Expand: Cancer and the Cell Cycle
Cancer is the result of unchecked cell division caused by a breakdown of the mechanisms that regulate the cell cycle. The loss of control begins with a change in the DNA sequence of a gene that codes for one of the regulatory molecules. Faulty instructions lead to a protein that does not function as it should. Any disruption of the cell cycle can allow other mistakes to be passed on to the daughter cells. Each successive cell division will give rise to daughter cells with even more accumulated damage. Eventually, all checkpoints become nonfunctional, and rapidly reproducing cells crowd out normal cells, resulting in a tumor or leukemia (blood cancer).
The genes that code for the positive cell-cycle regulators are called proto-oncogenes. Proto-oncogenes are normal genes that, when mutated in certain ways, become oncogenes — genes that cause a cell to become cancerous. Consider what might happen to the cell cycle in a cell with a recently acquired oncogene. In most instances, the alteration of the DNA sequence will result in a less functional (or non-functional) protein. The result is detrimental to the cell and will likely prevent the cell from completing the cell cycle; however, the organism is not harmed because the mutation will not be carried forward. If a cell cannot reproduce, the mutation is not promoted and the damage is minimal. Occasionally, however, a gene mutation causes a change that increases the activity of a positive regulator.
Tumor Suppressor Genes
Like proto-oncogenes, many of the negative cell-cycle regulatory proteins were discovered in cells that had become cancerous. Tumor suppressor genes are segments of DNA that code for negative regulator proteins, the type of regulators that, when activated, can prevent the cell from undergoing uncontrolled division. The collective function of the best-understood tumor suppressor gene proteins — retinoblastoma protein (Rb), p53, and p21 — is to put up a roadblock to cell-cycle progression until certain events are completed. A cell that carries a mutated form of a negative regulator might not be able to stop the cell cycle if there is a problem. Tumor suppressors are similar to brakes in a vehicle; malfunctioning brakes can contribute to a car crash!
Mutated p53 genes have been identified in more than 50 percent of all human tumor cells. This discovery is not surprising considering the multiple roles that the p53 protein plays at the G1 checkpoint. A cell with a faulty p53 may fail to detect errors present in the genomic DNA. Even if a partially functional p53 does identify the mutations, it may no longer be able to signal the necessary DNA repair enzymes. Either way, damaged DNA will remain uncorrected. At this point, a functional p53 will deem the cell unsalvageable and trigger programmed cell death (apoptosis). On the other hand, the damaged version of p53 found in cancer cells cannot trigger apoptosis.
The loss of p53 function has other repercussions for the cell cycle. Mutated p53 might lose its ability to trigger p21 production. Without adequate levels of p21, there is no effective block on cyclin-dependent kinases activation. Essentially, without a fully functional p53, the G1 checkpoint is severely compromised and the cell proceeds directly from G1 to S regardless of internal and external conditions. At the completion of this shortened cell cycle, two daughter cells are produced that have inherited the mutated p53 gene. Given the unfavorable conditions under which the parent cell reproduced, it is likely that the daughter cells will have obtained other mutations in addition to the faulty tumor-suppressor gene. Cells such as these daughter cells quickly accumulate both oncogenes and non-functional tumor-suppressor genes. Again, the result is tumor growth.
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- Question 1 of 3
Many of the negative regulator proteins of the cell cycle were discovered in what type of cells?CorrectIncorrect
- Question 2 of 3
_______ are changes to the order of nucleotides in a segment of DNA that codes for a protein.CorrectIncorrect
- Question 3 of 3
A gene that codes for a positive cell-cycle regulator is called a(n)…CorrectIncorrect
Additional Resources and Readings
An Amoeba Sisters video covering the cell cycle and cancer
An interactive graphic allowing you to explore the phases, checkpoints, and protein regulators of the cell cycle
An interactive activity on how cancer grows
- cell-cycle checkpointsmechanism that monitors the preparedness of a eukaryotic cell to advance through the various cell-cycle stages
- cyclin-dependent kinases (Cdk)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
- cyclinsone 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
- oncogenesmutated version of a normal gene involved in the positive regulation of the cell cycle
- p21cell-cycle regulatory protein that inhibits the cell cycle; its levels are controlled by p53
- p53cell-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
- proto-oncogenesnormal gene that when mutated becomes an oncogene
- retinoblastoma protein (Rb)regulatory molecule that exhibits negative effects on the cell cycle by interacting with a transcription factor (E2F)
- tumor suppressor genessegment of DNA that codes for regulator proteins that prevent the cell from undergoing uncontrolled division
License and Citations
Authored and curated by Jill Carson for The TEL Library. CC BY NC SA 4.0
Title: Biology – 10.3 Control of the Cell Cycle – Regulation of the Cell Cycle by External Events: Rice University, OpenStax CNX. License: CC BY 4.0
Title: Biology – 10.4 Cancer and the Cell Cycle – Proto-oncogenes: Rice University, OpenStax CNX. License: CC BY 4.0
|Figure 1. Cell Cycle||OpenStax||OpenStax||CC BY 4.0|
|American journal of roentgenology||Internet Archive Book Images||Wikimedia Commons||Public Domain|
|LMC-1||Dr Ramon Simon-Lopez||Wikimedia Commons||Public Domain|
|Fruit fly larva and pupae 01||Unknown||Wikimedia Commons||CC BY 2.5|