Cell Cycle Control

Background: The ideas on this page overlap with the information presented in Campbell, Chapter 12: The Cell Cycle. Campbell has an excellent description of mitosis and a good overview of cell cycle checkpoints. However, I think there's room for improvement in Campbell's presentation of the regulation of checkpoints by cyclin and CDK. The graphs of cyclin levels and MPF activity reflect a classic piece of the history of biology, but don't necessarily reflect the most current thinking on these topics. I want to present a slightly different approach to this topic, which will emphasize its relevance to the biology of cancer and aging. I have two pages on cell cycle topics:

The cell cycle

Your body made itself, starting from a single cell and developing to become an integrated multicellular organism comprising tens of trillions of cells. The process of development is fantastically complex, but it comes down to two fundamental kinds of events: cell proliferation, to make new cells, and differentiation, to give those cells the appropriate functional identity.

Both cell proliferation and differentiation can be described as information processing systems. In both cases, most of the functions of cells are controlled by the activities of specific proteins, and the functions of those proteins are either controlled directly (for example, by allosteric regulation) or indirectly, through gene expression control. On this page, I’ll describe how cell proliferation is controlled at the levels of proteins and gene expression.

For cells to grow and divide successfully, they must perform a series of steps, all in the right order. Those steps are called the cell cycle. For example, the cell must grow large enough before it can divide. It must completely copy its DNA before it begins mitosis, and it must accurately align the copied chromosomes before separating them. The whole cell cycle can be summarized in a few words: grow, then divide; it occurs in distinct phases.

Mitosis and interphase

Mitosis is the part of the eukaryotic cell cycle in which the chromosomes get separated and the cell prepares to divide. Generations of biology students have memorized the stages of mitosis, and having that knowledge helps you understand how cells divide. However, it's also helpful to have a historical perspective on it. Mitosis was first described when microscopes were almost the only tool available for cell biologists. Under the microscope, it's clear that there is a lot happening during mitosis: you can see the chromosomes organize themselves and move, and you can see one nucleus, and one cell, become two. The events of mitosis were divided into descriptive stages, as you can see on the diagram below.

Interphase refers to the rest of the rest of the cell cycle. It was so named because it looked like the long, uninteresting hiatus between cell division events. There's a phase during which DNA is synthesized (S phase), and the phases before and after DNA synthesis were called G, or gap phases — periods in which nothing seemed to be happening. Now we know better. Modern biologists have a lot more tools available, and we now know that many of the critical events that determine the fates of cells happen during interphase. They're invisible under conventional microscopes, but they have been explored with the tools of biochemistry and molecular biology. This has been part of a shift in how we look at all of biology: the science has moved from simply describing the visible events to explaining how they are controlled.

On this page, I'll describe the phases, but focus mainly on the control mechanisms.

Stages of the cell cycle

Mitosis stages

Look closely at the figure in Campbell called Exploring mitosis in an animal cell; it has excellent graphics and description. My simple diagrm above summarizes that one.

You should know the basics of the stages of mitosis for Bio 6B:

The cell transitions from interphase to mitotic phase. Chromatin begins to condense. In interphase, the chromatin (DNA with bound histones and other proteins) is decondensed, or spread out. This makes the DNA accessible for transcription and for DNA replication. However, the chromatin must be tightly condensed for the individual chromosomes to be moved around in mitosis. In the tightly condensed chromatin of mitosis, most DNA is not available for transcription. Chromosomes are always present in cells, but they are only visible as separate structures when they are condensed during mitosis.
Nucleoli (structures that produce ribosomes, inside the nucleus) disappear.
The mitotic spindle, composed of microtubules that will help move the chromosomes around, begins to assemble.
The nuclear envelope, which consists of two membranes, is broken down into multiple vesicles, which are moved out of the way.
The chromosomes are fully condensed. The two identical copies of each chromosome are still attached to each other; they are called sister chromatids.
The mitotic spindle begins to form two poles, organized by the two centrosomes.
Mitotic spindle microtubules attach to each chromosome at the kinetochore, a molecular motor that will move the chromosomes.
The centrosomes are at opposite poles of the cell, organizing the mitotic spindle into two poles.
Condensed chromosomes are pulled into alignment in the center of the cell, on the imaginary metaphase plate.
Sister chromatids become separated when the cohesin proteins that connect their centromeres break apart. The sister chromatids are now called daughter chromosomes.
At the end of anaphase, there should be a complete set of chromosomes at each end of the cell.
Returns the cell to interphase. The nuclear envelope reforms, chromatin decondenses,  the mitotic spindle disassembles.
The cell divides. The diagram above shows animal cells dividing by forming a cleavage furrow that eventually pinches the cell in two; plant cells, with their cell walls, use a very different approach. Cytokinesis begins before telophase is complete.

It's somewhat arbitrary how the phases are defined; older editions of Campbell didn't include prometaphase as a separate phase. More important than the names of the phases are the specific events that have to happen for cells to replicate and divide.

Interphase stages

Interphase also encompasses a set of specific events, but they’re less visible under a microscope. Interphase is when cell growth, DNA replication, gene expression and numerous other events occur. Interphase is divided into several phases:

G1 Phase
The part of interphase before DNA synthesis begins. Rapid cell growth occurs in this stage. Newly divided cells emerging from mitosis are usually small, so growth is needed to restore them to the original cell size. Proliferating cells must duplicate their organelles, proteins and other cell components; that duplication process begins in G1 phase.
G0 Phase
Cell cycle arrest; cells in G0 have exited the cell cycle. This phase could also be considered an indefinite continuation of G1. Cells in G0 don't proliferate, but they can live for many years and perform all their normal cellular functions. The vast majority of your cells are currently in G0 phase. Most of these cells are capable of restarting the cell cycle and moving to the next phase (S phase) if they receive the proper signals.
You might recall looking at microscope slides of animal tissues in Bio 6A. In a typical tissue, you can recognize that almost all the cells are in interphase, because they have decondensed chromatin and a clearly defined nucleus. Very few cells are in mitotic phase, partly because mitotic phase doesn't last very long, and partly because most cells are in cell cycle arrest, stuck in interphase.
S Phase
The period when DNA is replicated. The other activities of interphase (G1 and G2) occur continuously, but S phase is clearly defined by DNA replication. The beginning of S phase represents a commitment; there is no reason for a cell to start copying its DNA unless it is committed to completing the process and then performing mitosis.
G2 Phase
The part of interphase after DNA replication is completed. The cell continues to grow and synthesize cell components. Most cell growth processes occur continuously throughout interphase, so G1 and G2 aren't clearly separated phases with separate processes. However, each phase has its own checkpoint, which will be described below.

Each time a cell finishes a phase of the cell cycle, it needs to ensure that the everything is ready to go before it moves on to the next phase. This process of quality control operates though cell cycle checkpoints.

Cell Cycle Checkpoints

Cell cycle checkpoints ensure that each stage of the cell cycle is completed before the next stage begins. At each checkpoint, specific conditions must be met before the next stage begins. Since there are numerous cell cycle events that must be coordinated, there are multiple checkpoints, but here are three of the most important checkpoints:

Cell cycle clock with checkpoints

G2 & M checkpoints

The G2 and M checkpoints verify that critical processes of chromosome replication and division are happening correctly. The G2 checkpoint ensures that DNA replication is complete before mitosis begins; if mitosis starts too soon, the cell will end up producing daughter cells that are missing part of the genome. The M (mitosis, or metaphase) checkpoint ensures that the chromosomes are properly aligned with the metaphase mitotic spindle so they can be separated into two equal sets. If these criteria aren’t met, the cell cycle stops and repair processes are initiated.

G1 checkpoints

Checkpoints in G1 phase play a fundamental role in determining the fate of each cell in an animal’s body. The next step after G1 is S phase, defined by the beginning of DNA replication. A cell shouldn’t begin copying its DNA unless it’s going to complete the process and go on to divide; having partially copied DNA, or DNA that was copied but not divided, is likely to cause big problems with gene expression. So the decision to leave G1 phase and enter S phase is an important commitment point. It’s sometimes called the Restriction Point in the cell cycle. Passage through this checkpoint depends on a variety of factors. Unlike the G2 and M checkpoints, the G1 checkpoint doesn’t only check for internal errors, it also relies on signals sent from other cells. At the G1 checkpoint, it’s not just a matter of whether the cell is ready to start the next phase, it’s also a question of whether the body needs cells to be produced at that time and place.

Most of the cells in your body are stopped at the G1 checkpoint. You don't need all your cells to be continuously proliferating; if they did, you'd have twice as many cells tomorrow as you do today. Cells that are stopped at the G1 checkpoint enter G0 phase, or cell cycle arrest.

There is actually more than one checkpoint in the G1 phase (which is why this section is called "G1 Checkpoints"), but I’m only going to describe one.

Checkpoint Mechanisms

Checkpoints are controlled by Cyclin and CDK

Checkpoints with cyclin and CDK

Passage through each checkpoint is controlled by a specific pair of proteins: a cyclin and a cyclin-dependent kinase (CDK). Kinases phosphorylate other proteins, activating or inactivating them; this is how many biochemical pathways are controlled. At cell cycle checkpoints, the cyclin-dependent kinases phosphorylate their target proteins, activating them to begin the processes of the next phase of the cell cycle. Cyclin-dependent kinases are only active when bound to cyclin. Thus, cyclin and CDK form a partnership to control the cell cycle.

Cyclin is produced when the cell receives the appropriate signals to pass through the checkpoint, activating the CDK. Once the cell passes through the checkpoint, the cyclin is typically destroyed, leaving the inactivated CDK. The CDK can become active again when more cyclin is produced. Cyclin was originally named because it accumulates just before the cell passes a checkpoint, and then disappears after the checkpoint.

If cyclin/CDK controls the cell's progress through a checkpoint, then what controls cyclin/CDK? Each checkpoint requires a specific cyclin/CDK combination, controlled by specific events within the cell. There are numerous cyclins and CDKs, controlled in different ways, but I will present just a few examples.

Checkpoint information controls Cyclin & CDK

Each checkpoint checks for specific signals to determine whether the cell will continue with the cell cycle. Those checkpoint signals determine whether the cyclin/CDK complex will be activated.

Cyclin regulation

Progress through the cell cycle depends on dozens of factors, both internal and external to the cell. All these factors somehow regulate the activity of cyclin and CDK, which together act as the “switch” that determines whether a cell passes to the next phase. The active cyclin/CDK complex for each checkpoint phosphorylates a specific set of enzymes needed for the next phase, setting in motion all the processes necessary for cell proliferation. Cyclin/CDK complexes also activate a pathway for ubiquinating and ultimately destroying cyclin itself. Thus the cell progresses through the checkpoint, but won't pass through the same checkpoint again until it receives a new proliferation signal.

I will give two specific examples of signals that control cyclin/CDK activity at specific checkpoints: one that acts as a “go” signal, activating cyclin/CDK and pushing the cell through the checkpoint, and one that acts as a “stop” signal, blocking cyclin/CDK.

Growth factors stimulate cyclin/CDK activity

Growth factors are signaling molecules (typically proteins) that are released from one cell and stimulate other cells to proliferate. In animals (including humans), this kind of communication is critical for determining how much cell proliferation should occur. Growth factor concentrations are normally kept very low, but increase when more cell proliferation is needed in a particular tissue.

Ras signaling pathway

This diagram shows a simplified version of a pathway for Epidermal growth factor (EGF):

  1. Epidermal growth factor (EGF) is a small protein that signals cells to proliferate. EGF binds to a growth factor receptor, a transmembrane protein. Binding of EGF activates the receptor protein, which in turn initiates a process of signal transduction, in which the signal from outside the cell (EGF) is converted to another kind of signal inside the cell.
  2. Once it's activated by the growth factor, the receptor activates a signaling protein inside the cell, called Ras.
  3. Activated Ras phosphorylates a protein kinase, activating it. The activated protein kinase, in turn, phosphorylates a different kinase, which phosphorylates yet another kinase. This series of events is called a phosphorylation cascade. (In the diagram, I only showed one kinase, but there are several.)
  4. Finally, the last kinase in the cascade phosphorylates a protein called myc. Once it's phosphorylated, myc enters the nucleus.
  5. Inside the nucleus, myc acts as a transcription factor, upregulating transcription of several proliferation-related genes.
  6. One of the genes upregulated by myc is Cyclin D.
  7. Cyclin D is transcribed, then translated in the cytoplasm, and finally activates a specific cyclin-dependent kinase (CDK). The active cyclin/CDK complex then phosphorylates a variety of proteins, activating them and sending the cell into the next phase of the cell cycle. Since this is a G1 checkpoint, the next steps involve preparing for DNA synthesis.

There are a lot of steps in this pathway, and this is actually a greatly simplified version. The real pathway is complex; it integrates multiple cellular signals and ultimately controls the expression of multiple genes. Don't get bogged down in the details, just focus on the outcome. Growth factor binds to its receptor, starting a phosphorylation cascade that leads to cyclin transcription and passage through the checkpoint. You don't need to memorize the names of all the proteins.

DNA damage blocks cyclin/CDK activity

When a cell’s DNA is damaged, it’s important to stop cell proliferation. Such damage can be caused by mutagens such as ultraviolet light or chemicals, by reactive oxygen species (ROS), or can result from errors in replication or other processes. DNA damage changes the conformation of chromatin, which activates several enzymes as part of a DNA damage response,  stopping the cell cycle and triggering either repair or destruction of the cell. This ensures that the cell won't pass on its damaged DNA.

p53 DNA damage pathway

There are several pathways involved in the DNA damage response; this diagram shows a pathway involving the tumor suppressor p53.

  1. DNA damage directly activates DNA-binding damage response proteins.
  2. The protein ATM gets phosphorylated, and activated, by DNA-binding proteins.
  3. Activated ATM phosphorylates p53. If p53 isn't phosphorylated, it gets destroyed. In its phosphorylated state, p53 is resistant to being destroyed.
  4. Phosphorylated p53 acts as a transcription factor, upregulating the expression of specific genes by helping RNA polymerase bind to the promoters. The protein p53 (along with its gene) is also called a tumor suppressor, because the genes it controls tend to stop the cell cycle and initiate DNA repairs, preventing tumor formation.
  5. One of the target genes upregulated by p53 is called p21, which is also a tumor suppressor.
  6. After the p21 gene is transcribed, the p21 mRNA leaves the nucleus and gets translated by ribosomes in the cytoplasm. The p21 protein directly binds to cyclin/CDK complexes, blocking their activity and stopping the cell from passing through the checkpoint. This response can occur at more than one checkpoint.

The protein (and gene) p53 plays a central role in cell cycle control. Whenever there is DNA damage or other cellular stress, p53 is activated, turning on genes that stop the cell cycle, initiate repair processes, and in some cases initiate apoptosis (programmed cell death, described below). For this reason, p53 is sometimes called the guardian of the genome.

Telomere shortening blocks the cell cycle

Telomere DNA normally forms loops on the ends of eukaryotic chromosomes. The overhanging single-stranded end of the chromosome folds over and forms a loop, which is held together by specific proteins. As a cell line goes through multiple cell divisions, its telomeres become shorter and shorter, until they can no longer form the loop. This leaves exposed DNA ends on the chromosomes, activating p53 and blocking the cell cycle. In this situation, the end result is often replicative senescence, meaning that the cells are permanently blocked from proliferating. Cells that have entered replicative senescence are stuck in G0 phase indefinitely. Replicative senescence may limit our lifespan, but it also protects us against cancer.

Apoptosis can destroy DNA-damaged cells

The cell cycle control system is both a system for ensuring that an appropriate amount of cell proliferation occurs and a system of quality control, allowing only cells with undamaged DNA to proliferate. Like the protein quality control system that you learned about earlier this quarter, there are two possible responses to DNA damage: repair the DNA or destroy the cell in a process called apoptosis, or programmed cell death.

Apoptosis and blebbing

When a cell undergoes apoptosis, the cell’s own enzymes are activated to break down both proteins and nucleic acids. Mitochondria and other membrane-bound structures are dismantled, and eventually the cell is broken into numerous “blebs,” which are membrane-bound structures containing degraded macromolecules. This  ensures that potentially harmful mutated DNA is eliminated, and allows the cell’s molecular components to be recycled by other cells.

Here’s an excellent video on apoptosis, from Elvire Thouvenot-Nitzan.

Since apoptosis is the cell's ultimate response to a wide range of problems, it can be activated in more than one way.

Apoptosis can be triggered through an extrinsic pathway

In some cases, a cell can be induced to undergo apoptosis by a signal from another cell. For example, T cells of the immune system can trigger damaged or infected cells to undergo apoptosis. This is called an extrinsic pathway of apoptosis, because it’s triggered from outside the cell. There are also other extrinsic apoptotic pathways, for damaged or diseased cells, or as part of normal development when cells must be eliminated.

Steps of the extrinsic pathway:

  1. A “death signal” is received from another cell. One example of a death signal could be the binding of a cytotoxic T cell, which triggers other cells to perform apoptosis by way of the FasL ligand shown in the video above. The death signal activates a transmembrane receptor protein. (The word ligand refers to anything that activates a receptor.)
  2. The activated death signal receptor activates a caspase. Caspases are proteolytic (protein-cutting) enzymes that are involved in cell destruction during apoptosis. 
  3. The first caspase activates other caspases, which in turn activate others, in a process known as a caspase cascade.
  4. The activated caspases break down numerous cell components, leading to apoptotic destruction of the cell.

Intrinsic and extrinsic pathways of apoptosis

Apoptosis can be triggered through an intrinsic pathway

As shown in the “Stop signal” diagram on this page, DNA damage can activate a p53 tumor suppressor pathway that stops the cell cycle. Once the cell cycle is stopped, the cell can activate a DNA repair pathway to fix the damage and then restart the cell cycle. However, if the damage cannot be repaired, the cell may be triggered to perform apoptosis. This is called the intrinsic pathway of apoptosis, because it’s triggered from within the cell. In this example, the intrinsic pathway is initiated in response to DNA damage, but it can also be initiated by the accumulation of misfolded proteins (the unfolded protein response, or UPR) or other cell damage.

Mitochondria play an essential role in apoptosis. One of the early events of the intrinsic pathway is permeabilization of the  mitochondrial membranes, meaning that a variety of substances are allowed to pass through. One result is that the electrochemical proton gradient breaks down, which stops ATP synthesis and triggers various destructive processes. Another result is that cytochrome C is released, allowing it to perform a completely new role in the cytoplasm.

Steps of the intrinsic pathway: 

  1. DNA damage activates ATM, which in turn activates p53. These steps of the DNA response are the same for DNA damage and for cell cycle arrest and DNA repair.
  2. Depending on conditions in the cell, p53 may activate BAX, which attaches to the mitochondrial membrane and causes permeabilization, allowing various molecules to cross the membrane. During apoptosis, both the inner and outer membranes eventually get permeabilized. 
  3. With the outer membrane permeabilized, Cytochrome C is released. Cytochrome C is an electron carrier in the electron transport chain of cellular respiration. It is normally found in the intermembrane space, where it picks up electrons from complex III and passes them to complex IV (cytochrome oxidase). When the mitochondrial membranes break down during apoptosis, cytochrome C is released into the cytosol, where it finds a new protein partner waiting.
  4. In the cytosol, Cytochrome C binds to inactive subunits (called APAF-1) of the apoptosome. This induces the subunits to assemble into a functioning apoptosome, which is a destructive enzyme complex that initiates cell breakdown.
  5. The apoptosome activates caspases, which finish off the destruction of the cell.

In both the intrinsic and extrinsic pathways of apoptosis, the cell is destroyed by its own enzymes, including caspases. These destructive enzymes are normally present in cells in an inactive form, and can be quickly activated during apoptosis without the need for new protein synthesis. This ensures that cells can perform apoptosis even when the process of gene expression is disrupted due to genome damage. Apoptosis is a critical failsafe mechanism that protects us against cancer by eliminating dangerously damaged cells that cannot be repaired. In addition, apoptosis is an essential mechanism for eliminating unneeded cells from the body, both in animals and in plants.

In these diagrams, I’m showing two simplified pathways of apoptosis, but there are actually numerous overlapping pathways for inducing apoptosis in response to a wide range of cellular damage.

Cancer mutations disrupt checkpoints

Cancer is a range of diseases characterized by excessive cell proliferation. Each cancer is unique, arising from a set of genetic and epigenetic changes that ultimately deregulate the cell cycle, allowing a group of tumor cells to proliferate out of control and metastasize (spread to other areas of the body). Cancer cells typically acquire numerous mutations, but in general they must have changes in two categories of genes: tumor suppressors and oncogenes. Both of these categories of cancer-related mutations have the potential to disrupt the regulation of cell cycle checkpoints.

Tumor suppressors stop cell proliferation

As you have already seen, normal cell cycle control involves some genes and proteins that act to stop cell proliferation when appropriate. These genes are called tumor suppressors, because they tend to prevent tumors from growing.

Tumor suppressors in the p53 pathway.

The diagram above shows tumor suppressors p53, p21, and ATM (these names apply to both the proteins and the genes). These tumor suppressors stop cells from passing through cell cycle checkpoints if their DNA is damaged. Once a cell is stopped at a checkpoint due to DNA damage, either the damage is repaired or the cell is induced to perform apoptosis.

As long as all these tumor suppressor pathways are functioning, it's unlikely that cancer will develop. In fact, p53 exerts such a strong protective effect that the majority of cancers can only occur when mutations disrupt this pathway. Cancer cells typically have mutated, non-functional tumor suppressor genes. Such mutations are called loss-of-function mutations. Fortunately, our diploid cells have two copies of each locus. This means that if one copy carries a loss-of-function mutant allele, the other functioning copy of the gene may be able to cover for it, preventing excess cell proliferation. Cells are likely to turn into tumor cells only when both copies of a tumor suppressor locus have loss-of-function mutations.

Loss-of-function mutations can arise in several different ways. One possible mechanism, as you saw in the example of the pGLO non-fluorescent mutant, is a point mutation that introduces an extra stop codon into the protein. A mutation in a promoter or an enhancer can also prevent a gene from being expressed normally, causing loss of function.

Oncogenes encourage excess cell proliferation

Cell cycle control also involves positive proliferation signals, such as those illustrated in the growth factor pathway. The genes and proteins involved in proliferation signaling normally push cells through checkpoints only when the appropriate criteria have been met; they don't cause excessive cell proliferation. However, it's possible for those genes to become mutated so that the proteins send excessive growth signals.

Growth factor and oncogene pathways

A gene that sends signals causing excess cell proliferation is called an oncogene (onco- means cancer). In a normal cell proliferation pathway, such as the growth factor pathway shown above, the genes that encode proteins sending positive proliferation signals are called proto-oncogenes; if they become hyperactive, sending too much proliferation signal, they become oncogenes. A mutation that makes a gene (or its protein product) hyperactive is a gain-of-function mutation.

Gain-of-function mutations can arise in several different ways. For example, a point mutation in the protein-coding region could result in a protein that is active without being phosphorylated, binds more tightly to its normal partners, or is resistant to degradation. Alternatively, mutations in promoter or enhancer elements could cause the protein to be over-produced.

Other changes in cancer cells

Cancer is not a single disease; in some sense, every cancer is unique. Cancer cells start out as normal cells and become transformed through a series of genetic and epigenetic changes that ultimately lead to uncontrolled proliferation of a particular group of cells (a tumor). Each tumor cell line gets transformed through a unique evolutionary pathway, but tumor cells tend to have certain features in common:

  • Disrupted cell cycle checkpoint control through gain-of-function mutations in proto-oncogenes and loss-of-function mutations in tumor suppressors.
  • Loss of checkpoint control leads to an increased rate of mutation.
  • Resistance to apoptosis.
  • Altered hormonal signaling leading to excess proferation.
  • Angiogenesis: the growth of new blood vessels. Without a blood supply, a tumor won't  continue growing.
  • Aneuploidy: altered number of chromosomes, due to duplication or loss of a chromosome, or rearrangement of fragments of chromosomes. Aneuploidy may be a consequence of checkpoint disruption, or it may be a cause.
  • Alteration of energy pathways, including an increased dependence on fermentation over cellular respiration (the Warburg effect).
  • Escape from the immune system, which typically destroys abnormal cells.

Cancer represents a failure of systems that integrate the body's cells to work together as a multicellular organism. These mechanisms involve every aspect of gene expression and cell cycle control within cells, as well as the many mechanisms for signaling from one cell to another. There is still a lot of basic biology that we don't know, and will have to learn in order to continue to make progress in improving human health. In fact, much of what we now know about the basic biology of the cell cycle comes from research on cancer.

And it's not only about humans. Moving forward, perhaps some of the next big breakthroughs in biology will come from a comparative approach, asking how some other animals may do things quite differently from us, despite having similar sets of proteins. For more on this topic, turn to longevity, Peto’s paradox & zombie genes.


  • Progress through the cell cycle is controlled by checkpoints, at which specific criteria must be met before the the cell can progress to the next phase.
  • Cyclin and cyclin-dependent kinase (CDK) together control passage through the checkpoints. Checkpoint signals act to upregulate or downregulate the activity of cyclin/CDK complexes.
  • DNA damage activates a pathway to block cell proliferation by inhibiting cyclin/CDK activity.
  • Growth factors activate a pathway to increase cell proliferation. Growth factor receptor activation activates a phosphorylation cascade, which ultimately phosphorylates the transcription factor myc, which upregulates transcription of cyclin.
  • Genes (and proteins) that help put the brakes on the cell cycle are tumor suppressors. Cancer cells often have loss-of-function mutations in tumor suppressors.
  • Genes that encourage cell proliferation are proto-oncogenes. Cancer cells often have gain-of-function mutations in proto-oncogenes, turning them into oncogenes.

Cell cycle control pathways summary.

This diagram summarizes two pathways described on this page: the p53 pathway that stops cell proliferation, and the growth factor pathway that encourages it. Notice the things that both these pathways have in common:

  • Both act on cyclin/CDK activity to control the cell cycle.
  • Both are mediated by phosphorylation cascades, in which one protein gets phosphorylated and then phosphorylates another.
  • Both ultimately phosphorylate transcription factors, upregulating transcription of genes involved in cell cycle control.

In the diagrams on this page, I've shown greatly simplified versions of some of the pathways involved in regulating the cell cycle. The cell cycle is actually regulated by a complex network of interactions, involving dozens of proteins, but many of those pathways converge on a few critical points, including cyclin, CDK, and p53. Cell cycle control is one of the main information processing activities of every cell, along with gene expression and energy metabolism. All these pathways interact to determine the fate of every cell.


Terms & Concepts

  • Anchorage dependence and density-dependent inhibition: See Campbell for a description of these terms.
  • Apoptosis
  • Apoptosome
  • Blebbing
  • Caspases
  • Cell cycle arrest (G0 phase)
  • Cell proliferation
  • Centromere: region in the middle of the chromosome.
  • Centrosome: organizing center for mitotic spindle.
  • Checkpoints
  • Chromatin: condensed and decondensed
  • Chromosomes. They are always present in the cell, whether they are condensed or not.
  • Cyclin
  • Cyclin-dependent kinase
  • Cytochrome C
  • DNA damage response
  • Growth factors
  • Interphase
  • Intrinsic and extrinsic pathways of apoptosis
  • Kinase
  • Kinetochore. See Campbell for this.
  • Loss-of-function mutations & gain-of-function mutations
  • Oncogene and proto-oncogene
  • p53
  • Phases of mitosis
  • Phosphorylation
  • Ras
  • Replicative senescence
  • Restriction point (G1 checkpoint)
  • S phase
  • Sister chromatids
  • Transcription factor
  • Tumor suppressor

Cyclin & CDK in Campbell

The section in Chapter 12 called "The cell cycle clock: cyclin and cyclin-dependent kinases" can be a little misleading. The diagrams and text describe a structure called MPF. The term MPF was used to describe an unknown entity, years before the discovery of cyclin and CDK. Eventually, researchers discovered that MPF is actually a particular combination of a cyclin and a CDK; now we know that there are also other cyclins and CDKs. The term MPF is no longer commonly used; it's a piece of history. This diagram shows one cyclin/CDK pair, labeled MPF, but there are multiple cyclin/CDK pairs, acting at different checkpoints.

Also, the diagram in Campbell indicate sthat cyclin is continually produced at a constant rate, but this is only true during rapid cell proliferation, such as in the synchronized cell divisions of the early embryos of sea urchins, in which cyclin was first discovered. Most of the time, cyclin expression is regulated by various signals and doesn't occur at a constant rate. If you are curious about the history, you might want to look at the original paper describing the discovery of cyclin.

Names of proteins

Numerous proteins are mentioned on this page; you don't need to memorize all their names. First try to understand the pathways without the names. I hope you can remember cyclin and CDK, but don't try to remember which ones act at which checkpoints. Remember p53, since it occupies such a central role. If I refer to others, like Ras, myc, ATM, or p21, in test questions, I'll give you strong hints about what they do.

Keep in mind that the same name applies to both the gene and the protein it encodes. There are formatting rules to distinguish them (for example, genes are usually italicized, while proteins aren't), but I'll try to explicitly distinguish them when necessary. If we say something like, "p53 is a tumor suppressor," that statement applies to both the gene and its protein product.

Review questions

  1. In the cell cycle, when is the chromatin condensed, and when is it decondensed? Why?
  2. When are chromosomes present in a cell? When are they visible separate structures?
  3. When are sister chromatids present in a cell?
  4. What do cyclin-dependent kinases do? How are they activated?
  5. Explain the DNA damage response. Why is it important that the cell cycle is stopped when DNA damage is detected? How is cell cycle arrest triggered in response to DNA damage? How is this cell cycle arrest connected to cyclin-dependent kinase activity? How is DNA damage connected to apoptosis?
  6. How do growth factors trigger cell proliferation? How is growth factor signaling connected to cyclin-dependent kinase activity?
  7. Explain the role of mitochondria in apoptosis.
  8. Why do we need tumor suppressors? What do tumor suppressor pathways normally do other than suppress tumor growth? How is tumor suppressor activity connected to cyclin/CDK activity? Give several examples of tumor suppressor genes (and proteins) from this page.
  9. Why do we have proto-oncogenes? How do they interact with cyclin/CDK? Give several examples of proto-oncogenes from this page.
  10. How can a proto-oncogene be turned into an oncogene?
  11. Give two examples of transcription factors that help control the cell cycle. How are these transcription factors activated, and what do they do to control the cell cycle?
  12. Suppose there is a mutation that changes the nucleotide sequence of the promoter for the p21 gene, so that p53 can't bind to this promoter. How would that mutation affect the cell cycle? Is this an oncogene pathway, a tumor suppressor pathway, or neither? Would this mutation be a loss-of-function mutation, gain-of-function, or neither?
  13. Suppose there is a mutation that changes the nucleotide sequence of the promoter for the Cyclin D gene, so that myc can't bind to this promoter. How would that mutation affect the cell cycle? Is this a proto-oncogene pathway, a tumor suppressor pathway, or neither? Would this mutation be a loss-of-function mutation, gain-of-function, or neither?
  14. How many different examples of kinase activity can you find on this page?

References & further reading

Cell cycle control

Cyclin and Cyclin-dependent Kinase from PDB-101. A close look at the proteins.

Cell cycle regulators article from Khan Academy.

Cell Growth Control from a project at Yale. This page provides a clear and detailed explanation; more detail than you need for Bio 6B.

p53 and related pathways

The p53 Gene and Cancer HHMI Biointeractive.

This protein is mutated in half of all cancers. New drugs aim to fix it before it’s too late. Science Magazine, 2016.

Cell Cycle and DNA Damage Repair Poster from Tocris. Shows some of the pathways involved in cell cycle control, including p53, p21, ATM, cyclin, and others. From a company that cells molecular biology research products.

Putting p53 in Context. Kastenhuber & Lowe, 2017. Cell. "p53 is activated by a host of stress stimuli and, in turn, governs an exquisitely complex anti-proliferative transcriptional program that touches upon a bewildering array of biological responses." This review article gives an outstanding overview of the many biological effects of p53. Magnificent diagrams (don't miss the fabulous Swiss army knife!).


"What is Apoptosis?" The Apoptotic Pathways and the Caspase Cascade. YouTube. This is the video embedded on this page. Excellent animation and description of apoptosis pathways.

Apoptosomes. PDB-101. I used the apoptosome diagram from this page, which gives a good overview of apoptosome structure and function. See also Caspases and Cytochrome C on the same site.

DNA damage response pathway (advanced)

The DNA Damage Response Mediates Apoptosis and Tumor Suppression. Baran & Rodriguez, 2013. Way more than you need for Bio 6B, but this well-written review article clearly describes the various important roles of the DNA damage response.

Targeting the DNA Damage Response in Cancer. O'Connor, 2015. Molecular Cell. This scientific review article highlights the importance of cellular responses to DNA damage in health and in cancer treatment. As a Bio 6B student, you could work your way through this. It wouldn't be easy, but you could do it.

Cyclin/CDK pathways (advanced)

Biochemical pathways are complex, and cell cycle regulation by cyclin/CDK is connected to most other activities that happen in cells. These articles give some insight into the wide range of interactions involving these proteins.

Cdks, cyclins and CKIs: roles beyond cell cycle regulation. Lim, 2013. "In addition to their well-established function in cell cycle control, it is becoming increasingly apparent that mammalian Cdks, cyclins and CKIs play indispensable roles in processes such as transcription, epigenetic regulation, metabolism, stem cell self-renewal, neuronal functions and spermatogenesis. Even more remarkably, they can accomplish some of these tasks individually, without the need for Cdk/cyclin complex formation or kinase activity."

Cell cycle transcriptomics of Capsaspora provides insights into the evolution of cyclin-CDK machinery. Perez-Posada, 2020. The authors studied cyclin-CDK pathways in a unicellular organism to gain insight into the evolution of the more complex pathways found in animals.

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