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contents Principles of Biology 33 Control Molecular controls monitor the progression of the cell cycle.

Cancer occurs when the cell cycle checkpoints somehow fail, which causes cells to divide out of control. The breast cancer cells above have become cancerous and have divided excessively throughout the breast tissue. This breast tissue is stained with dyes to show nuclei clearly (magnified 200X). Dr. Cecil Fox/National Cancer Institute.

Topics Covered in this Module

Overview of Cell Cycle Regulation Maturation­promoting Factor Was the First Complex Identified that Controls the Cell Cycle There Are Many in Cells

Major Objectives of this Module

Describe the molecular system that regulates progression through the cell cycle. Describe how cell cycle control mechanisms respond to internal and external signals. Explain how cancers result from breakdowns in cell cycle control.

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contents Principles of Biology

33 Cell Cycle Control

Overview of Cell Cycle Regulation In a adult, skin cells divide continuously, whereas cells divide only in response to injury, and muscle cells repair themselves but cannot divide. Cells clearly differ in their ability to divide continuously, occasionally, or never again after being formed. Why? What tells a cell whether to progress through the cell cycle or stop?

In the 1970s, scientists investigated this question by fusing cells in culture that were in different stages of the cell cycle. If one cell was in G1 and the other in S, the G1 cell's nucleus began synthesizing DNA just like the second cell's nucleus. If one cell was in G1 and the other in , the G1 nucleus went straight into mitosis (Figure 1). What could this mean? The scientists hypothesized that signals in the were instructing the nucleus what to do.

Figure 1: Cell cycle controls. Fusing a dividing cell with a cell at rest causes the resting cell to enter . Human cells in the G1, S, or are fused with cells in the M phase. Premature condensation can be seen when a cell in the M phase is fused with a) one cell in the or b) two cells in the G1 phase. Premature chromosome condensation occurs when an M­phase cell is fused with c) an S­phase cell and d) when a cell is blocked at the G1­S boundary by chemical treatment. Premature chromosome condensation is observed in e) an M­ phase cell fused with a cell in the G2 phase. In panel f) the show characteristics of all three original cells when a cell is formed from the fusion of three cells in the G1, G2, and M phases. (Notice the arrows. G1 chromosomes are thin threads, G2 chromosomes are thicker and more condensed, and M chromosomes are short, thick, and rod­ like). © 1970 Nature Publishing Group Johnson, R.T. & Rao, P.N., Mammalian cell fusion: induction of premature hromosome condensation in nuclei. Nature 226, 717–722 (1970) doi: 10.1038/226717a0. Used with permission. Figure Detail

Research has since revealed that external signals as well as molecular signals within the cell can move a cell into a later phase of its cycle or cause it to pause. The system that controls which phase a cell is in is called the cell cycle control system. The times at which the cycle can be stopped or pushed forward are called checkpoints. By default, animal cells stop at the checkpoint, the way you would stop at the stadium gate on the way into a game or concert. Once the ushers know that you have a valid ticket, and you're not a danger to the rest of the crowd, they let you enter. signaling pathways are the ushers that interact with molecules involved in the cell cycle, such as components of the DNA replication machinery and , to decide whether or not a cell should continue. If all the cellular processes that need to be completed before proceeding have been completed successfully and the environment seems favorable, then the cell passes through the checkpoint to the next phase.

At these checkpoints in the cell cycle, existing conditions are considered and the cell decides whether it is safe to proceed or stop and not divide (Figure 2). Checkpoints are at G1 (before the cell copies its DNA), G2 (before it enters mitosis), and M (before the sister chromatids separate), among other points. The most important checkpoint in mammals seems to be the G1 checkpoint. If the cell is not given the go­ahead at this point, it goes into and stops dividing. Most highly differentiated cells in the human body, including mature muscle cells and neurons, remain in G0. http://www.nature.com/principles/ebooks/principles­of­biology­104015/29145058/1 1/3 1/20/2015 Cell Cycle Control | Principles of Biology from Nature Education

Some cells, like liver cells, can leave G0 and reenter the cycle to repair an injury. If a cell passes through a G1 checkpoint, it usually goes on to complete mitosis. Growth and repair happen as needed. In some cases, such as in the liver, even if half of the organ is removed or damaged the remaining cells will divide to regenerate the whole organ.

Figure 2: Cell cycle regulation. For a cell to proceed through the phases of the cell cycle, certain protein signaling pathways must proceed to completion. The requirements for these pathways can be thought of as "checkpoints." These checkpoints prevent cells from reproducing under certain circumstances, such as if cells are injured, experience a malfunction during the stages of reproduction, or are not meant to reproduce. © 2012 Nature Education All rights reserved. Figure Detail

IN THIS MODULE

Overview of Cell Cycle Regulation Maturation­promoting Factor Was the First Complex Identified that Controls the Cell Cycle There Are Many Cyclins in Cells Summary Test Your Knowledge

WHY DOES THIS TOPIC MATTER?

Cancer: What's Old Is New Again Is cancer ancient, or is it largely a product of modern times? Can cutting­edge research lead to prevention and treatment strategies that could make cancer obsolete?

Stem Cells Stem cells are powerful tools in biology and medicine. What can scientists do with these cells and their incredible potential?

PRIMARY LITERATURE

The memory of iPS cells Incomplete DNA methylation underlies a transcriptional memory of somatic cells in http://www.nature.com/principles/ebooks/principles­of­biology­104015/29145058/1 2/3 1/20/2015 Cell Cycle Control | Principles of Biology from Nature Education human iPS cells. View | Download

Genetically­matched iPS cells more immunogenic than ES cells Immunogenicity of induced pluripotent stem cells. View | Download

Adaptor regulate cell signaling Structural basis for regulation of the Crk signaling protein by a proline switch. View | Download

The role of D1 in DNA repair linked to cancer growth A function for in DNA repair uncovered by protein interactome analyses in human cancers. View | Download

SCIENCE ON THE WEB

Follow the Cell Cycle An animated diagram of the cell cycle

The Nitty­gritty of Cell Cycle Control Read a Scitable article on cell cycle control and cancer

Targeted Therapy Watch a lecture on Gleevec, a cancer therapeutic targeting tyrosine receptor kinases

Discover more about Play this interactive to learn about "The Guardian of the Genome"

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contents Principles of Biology

33 Cell Cycle Control

Maturation­promoting Factor Was the First Complex Identified that Controls the Cell Cycle As the experiment in fusing cells indicated, the cell cycle is regulated substantially by proteins in the cell's cytoplasm. Many of the proteins involved in cell cycle regulation are cyclin­dependent kinases (Cdks). A cyclin is a protein whose concentration in the cell varies cyclically. A kinase is an enzyme that catalyzes the addition of a phosphate group to a molecule. Cdks are kinases whose activities are controlled by forming complexes with cyclins. Cyclin­Cdk complexes are formed from a protein kinase subunit and a cyclin subunit. When the two subunits associate, they form what is called the holoenzyme. In most cases, the concentration of the kinase subunit is relatively constant, whereas the concentration of the cyclin subunit oscillates. The kinase is completely inactive without its cyclin partner, but in addition to the formation of the cyclin­Cdk complex, activation of the holoenzyme requires the phosphorylation of a key residue in the kinase subunit. Test Yourself

How does the Cyclin­Cdk holoenzyme form, and how is it activated?

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The first cyclin­Cdk complex discovered — MPF or maturation­promoting factor — was found in frog eggs. The cyclin that is part of MPF is synthesized during the S and G2 phases (Figure 3). During G2, when this cyclin has reached critical concentration, it forms a complex with Cdk, producing MPF. MPF triggers mitosis by phosphorylating proteins, in some cases activating additional enzymes. It phosphorylates proteins in the nuclear envelope, promoting the nuclear envelope's breakdown during . MPF may also help chromosomes to condense and the mitotic spindle to form in prophase. In , MPF's actions cause its cyclin component to be broken down. The kinase remains in the cell in inactive form until new cyclin molecules are synthesized. The cyclin­Cdk complex then re­forms.

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Figure 3: Cyclin regulation of the cell cycle. One mechanism that regulates the cell cycle is the concentration of cyclin. Cyclin increases in concentration throughout the S and G2 phases. Near the end of the G2 phase, the cyclin molecules combine with a cyclin­ dependent kinase (Cdk), forming maturation­promoting factor (MPF). MPF is a holoenzyme that phosphorylates proteins needed for mitosis to proceed. If these proteins are not phosphorylated, the cell cycle halts at the M checkpoint. Cyclin is broken down during anaphase and must accumulate again for another round of mitosis to happen. © 2012 Nature Education All rights reserved. Figure Detail

Cyclins have been categorized into classes based on what phases of the cell cycle they regulate. For example, proteins regulate entry from the G0 to G1 phase and are found in the G1 phase. and B2 are part of the MPF that regulates mitosis or M­phase activities.

BIOSKILL Interpret a Concentration vs. Time Graph to Make Conclusions about the Progression of the Cell Cycle Determining when in the cell cycle certain kinases and cyclins peak provides clues that allow scientists to determine their functions. Examine Figure 4 to determine when cyclin and MPF peak.

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Figure 4: Control of the cell cycle. Peaks in levels of kinases and cyclins regulate the progression of the cell cycle. MPF peaks during mitosis. Cyclins gradually build up during G2 and drop again during mitosis. © 2014 Nature Education All rights reserved.

Test Yourself

Why do cyclin and MPF peak at the same time but rise at different rates?

Submit

BIOSKILL

IN THIS MODULE

Overview of Cell Cycle Regulation Maturation­promoting Factor Was the First Complex Identified that Controls the Cell Cycle There Are Many Cyclins in Cells Summary Test Your Knowledge

WHY DOES THIS TOPIC MATTER?

Cancer: What's Old Is New Again Is cancer ancient, or is it largely a product of modern times? Can cutting­edge research lead to prevention and treatment strategies that could make cancer obsolete?

Stem Cells Stem cells are powerful tools in biology and medicine. What can scientists do with these cells and their incredible potential?

PRIMARY LITERATURE

The memory of iPS cells Incomplete DNA methylation underlies a transcriptional memory of somatic cells in human iPS cells. View | Download

Genetically­matched iPS cells more immunogenic than ES cells Immunogenicity of induced pluripotent stem cells. View | Download

Adaptor proteins regulate cell signaling Structural basis for regulation of the Crk http://www.nature.com/principles/ebooks/principles­of­biology­104015/29145058/2 3/4 1/20/2015 Cell Cycle Control | Principles of Biology from Nature Education signaling protein by a proline switch. View | Download

The role of cyclin D1 in DNA repair linked to cancer growth A function for cyclin D1 in DNA repair uncovered by protein interactome analyses in human cancers. View | Download

SCIENCE ON THE WEB

Follow the Cell Cycle An animated diagram of the cell cycle

The Nitty­gritty of Cell Cycle Control Read a Scitable article on cell cycle control and cancer

Targeted Therapy Watch a lecture on Gleevec, a cancer therapeutic targeting tyrosine receptor kinases

PDliasyc othviesr imntoerrea catibvoeu tto p l5e3arn about "The Guardian of the Genome"

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contents Principles of Biology

33 Cell Cycle Control

There Are Many Cyclins in Cells There is a cyclin­Cdk complex in chicken cells that is similar to the complexes found in amphibian and mammalian cells. In Figure 5, the green color indicates , and the blue indicates DNA. Levels of cyclin B bound to cyclin­dependent kinase 1 (Cdk1) rise in interphase, but the complex is not activated until the end of G2 phase. Then it enters the nucleus, where it catalyzes condensation of DNA into chromosomes and breakdown of the nuclear membrane. Cyclin B breaks down during anaphase.

Figure 5: Changes in levels of cyclin B­Cdk1 complex over the cell cycle. In these chicken cells, DNA is stained blue, microtubules are stained red, and cyclin B is stained green (areas where microtubules and cyclin B are both present are yellow). Cyclin B–Cdk1 accumulates during interphase, is activated at the end of the G2 phase, and is degraded during anaphase. © 2008 Nature Publishing Group Hochegger, H., et al. Cyclin­dependent kinases and cell­cycle transitions: does one fit all? Nature Reviews Molecular Cell Biology 9, 910–916 (2008) doi: 10.1038/nrm2510. Used with permission. Figure Detail

Apart from the breaking down of the nuclear membrane and the condensing of chromosomes, what else happens at the beginning of mitosis? In addition to the control exerted by Cdk proteins, two more types of kinases, Polo­like kinases (Plks) and Aurora kinases, act at the M checkpoint. During mitosis and cytokinesis, they help regulate and prevent cell division errors, specifically centrosome duplication, assembly of the mitotic spindle, chromosome separation and cytokinesis. As with Cdks, Plks and Aurora kinases are also activated by phosphorylation (Figure 6).

Figure 6: Three different types of kinases. Cdk1, Plk1, and Aurora A are all part of a cascade that causes the mitotic spindle to start assembling toward the beginning of mitosis. Cdk1 activates the cofactor Bora by phosphorylating it. The kinase Aurora A, in the presence of http://www.nature.com/principles/ebooks/principles­of­biology­104015/29145058/3 1/8 1/20/2015 Cell Cycle Control | Principles of Biology from Nature Education

phosphorylated Bora, phosphorylates Plk1. Activated Plk1 then phosphorylates Nedd1, which combines with γ­ tubulin. Nedd1/γ­tubulin localizes to the centrosomes and enables assembly of the microtubules at the centrosome. © 2011 Nature Education All rights reserved. Test Yourself

What are Cdks, Plks and Aurora kinases, and what do they do?

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Which other steps of cell division might need to be regulated? At the M checkpoint, a complex of different proteins activates the enzyme "separase," which catalyzes the separation of sister chromatids. At this point in the cell cycle, it is crucial that the chromosomes be lined up at the plate with the sister chromatids facing in opposite directions, so that when the chromatids separate exactly one from each pair will go to each daughter cell. At the checkpoint, the cell checks whether each chromatid is attached to the mitotic spindle at its kinetochore. If some of the kinetochores are not attached to the spindle, anaphase does not start. If they are all attached securely, separase is activated and anaphase begins. Test Yourself

What happens at the M checkpoint in the cell cycle?

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There are also checkpoints during , when DNA duplication occurs. For instance, if replication is working properly, single­stranded DNA is rapidly turned into the more stable double­stranded form. Because single­stranded DNA is not very stable, certain proteins protect it during replication. One of these proteins, replication protein A, is also a trigger for an S phase checkpoint. If a lot of replication protein A is bound to DNA, the cell reads that as there being too much single­stranded DNA, a sign that the DNA may be damaged. This alters various interactions among replication protein A and other proteins involved in controlling DNA replication. DNA replication is halted while damage to the DNA is repaired.

Cdk­cyclin complexes also regulate the G1 checkpoint. Researchers have found three Cdk proteins and several cyclins active at this checkpoint. Cyclin D1 promotes and monitors during G1 by phosphorylating molecules. The cyclin D1 gene is called a proto­oncogene (which is a gene that can lead to cancer). Cyclin D1 is aberrantly expressed in a variety of tumors (more on this towards the end of this module). If too much cyclin D1 protein is present in a cell, the cell moves to S phase without pausing at the G1 and S checkpoints. This may lead to errors in DNA synthesis and cell division, which can initiate tumor formation.

Cell cycle control mechanisms respond to internal and external cues. As the researchers who discovered MPF hypothesized, the cell cycle responds to many internal signals. Is the kinetochore attached to the mitotic spindle? Is there too much single­stranded DNA? But the cell cycle also responds to external signals. Cell division is influenced by the availability of nutrients, growth factors and space to grow. If an essential nutrient becomes limiting, cells will stop dividing. Cells of most types of organisms also respond to specific growth factors, which are molecules that stimulate cell division. For instance, fibroblasts, connective tissue cells that produce collagen, will proliferate if the environment contains platelet­derived growth factor (PDGF). As its name suggests, PDGF is produced by platelets, which are involved in blood clotting. When you cut yourself, platelets not only help your blood clot but also release a growth factor that makes connective tissue cells grow to help heal the wound.

How does PDGF stimulate fibroblasts to grow? PDGF binds to specific receptors on the fibroblast . This triggers in the fibroblast a signal transduction pathway, which is a series of changes to different molecules that ultimately affects selected cellular functions. PDGF receptors are an example of receptor tyrosine kinases. Like other kinases, they catalyze phosphorylation. Each receptor spans the cell membrane, so it can communicate with the outside environment as well as the cell interior. Two PDGF molecules binding to two adjacent PDGF receptors causes the receptors to bind together (i.e., the receptors form a dimer). Each receptor phosphorylates its partner in the dimer. The phosphorylated PDGF receptor dimer now activates a series of other proteins. The newly activated proteins trigger additional pathways, which together push the cell through the G1 checkpoint into S phase.

How do cells react to the space around them? Many cells will stop dividing if they are too crowded. This phenomenon is called density­dependent inhibition (Figure 7). Cells in a Petri dish will keep dividing until a single layer of cells covers the surface of the dish, and then they will stop. If a scientist removes some cells, the cells will again start dividing until they fill in the gap. This inhibition occurs because proteins on the surfaces of neighboring cells bind to each other. Cell division keeps going while the surface proteins on some cells remain unbound but stops once all the cells have neighbors. Cancer cells, in contrast, may not show density­dependent inhibition. They may keep dividing despite crowding, forming multiple layers. The reason for the loss of this density­dependent inhibition may be that the cells produce additional external growth factors, or the cells may have abnormal signal transduction pathways that bypass normal growth checkpoints.

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Figure 7: Contact inhibition, a type of density­dependent inhibition. Panel a): Some types of normal cells will stop growing when they have covered one layer of a Petri dish. This is called contact inhibition. Panel b): When some of the cells are scraped away and removed, the cells that have lost contact with other cells will divide to re­establish cell­cell interactions. Panel c): Transformed cells can have disrupted cell­cell adhesion and a loss of contact inhibition. For example, cancer cells will keep growing even though the layer is full and the new cells cannot adhere to one another. © 2013 Nature Education All rights reserved.

What other conditions cause cell division to stop? Most animal cells divide only if attached to a surface; in the body, they attach to tissues. This phenomenon is called anchorage dependence. In cancer cells, anchor dependence may stop functioning, with the result that the cells keep dividing without needing to be anchored or attached at all. Specific cell functions other than cell division also show anchorage dependence. For instance, skin cells have vitamin D receptors. Skin exposed to sunlight produces vitamin D, which promotes the calcium absorption needed to maintain strong bones. Expression of the vitamin D receptor gene is normally anchorage­dependent (Figure 8).

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Figure 8: Anchorage dependence. A northern blot detecting RNA expression of the vitamin D receptor (VDR) gene. In a northern blot, bigger, darker bands indicate higher levels of RNA expression. The first block of bands (normal human epidermal keratinocytes, NHEKs) comes from normal human skin cells. The next two brackets (SCC12B2 and A431) indicate cancer cells. Adhesion (ADH) means that the cells were cultured on a surface (such as a Petri dish) during the experiment, and suspension (SUSP) means that no surface was provided for the cells to grow on. Gene expression was determined for each cell type in ADH conditions and after exposure to SUSP conditions for 24 or 48 hours. © 1998 Nature Publishing Group Segaert, S., et al. Anchorage­dependent expressions of the vitamin D receptor in normal human keratinocytes. Journal of Investigative Dermatology 111, 551–558 (1998) doi: 10.1046/j.1523­1747.1998.00367.x. Used with permission. Test Yourself

Look at the expression of the vitamin D receptor gene in the three cell lines under the three different conditions in Figure 8. Compare vitamin D receptor expression under conditions of adhesion (ADH) and suspension (SUSP) in normal skin cells (NHEK). Now look at the same conditions in the cancer cell lines SCC12B2 and A431. How are the cancer cells behaving differently than the normal cells?

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What happens when regulatory mechanisms fail? Cancer is the uncontrolled growth of abnormal cells in the body. How are cancer cells different from normal cells? They may not stop dividing when they are crowded or when they are free­floating. They may pass the G1 checkpoint into S phase without confirming that they are ready to do so. If they stop dividing, they stop at random points in the cycle, not at the usual checkpoints. A normal cell in culture will divide about 20–50 times before it dies through the process of , or programmed cell death. A cancer cell may divide more­or­less indefinitely, at least until the organism dies. Cells removed from a woman's tumor in 1951 are still dividing in culture today. They are called the HeLa cell line because the woman's name was Henrietta Lacks.

Although failure of any of several cell cycle controls can lead to uncontrolled growth, a single cell that has undergone this type of transformation into a cancer cell is usually recognized and destroyed by the immune system. If the immune system fails to catch the cell, it may proliferate in situ, in the place where it started. These cell masses form benign tumors, abnormal tissue growths that do not spread to other parts of the body. Benign tumors often do not cause serious health problems. If a benign tumor is causing problems by pressing against normal tissue — for example, pressing against the urethra and blocking urine flow — it can usually be surgically removed. People who have active cancer have malignant tumors. Malignant tumors contain cells that can spread to new tissues and proliferate in different parts of the body. This process is called metastasis. Multiple mutations are required for a cell to display both uncontrolled growth and metastasis. Mutations often accumulate over time before cancer develops.

Compared with normal cells from the same tissues, cancer cells look physically different. They are often less well differentiated and less clearly organized than normal cells because they have many mutations and proceed through the cell cycle without pausing at the normal checkpoints. How do the cancer cells in Figure 9 look different from the normal cells?

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Figure 9: Normal vs. cancerous tissue. The appearance of cancer cells depends on the tissues from which they originate. © 2012 Nature Publishing Group Left image: Nakamura, T. et al. 2004, http://www.nature.com; Right image: Ju Kang, H. et al. 2009, doi:10.1038/labinvest.2009.47. Used with permission. All rights reserved. Figure Detail

Cancer does not just occur in animals, can also have uncontrolled growth that results in cancerous tumors. Many of these types of tumors are induced by pathogens, such as bacteria, fungi and viruses (Figure 10). While the development of these tumors has many similarities to those that occur in animals, there are also many differences. For example, plant tumors tend to be more restricted and unable to spread because plants lack cell mobility, keeping tumors localized, and because most plant cells are able to differentiate into any type of tissue.

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Figure 10: Plant tumors. a) This tree is infected with Agrobacterium tumefaciens. The bacterial plant pathogen has caused crown gall disease in this tree. Leonard Lessin/Science Source.

Test Yourself

Can plants develop tumors? Why or why not?

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Specific cellular functions controlling normal cell division are impaired or knocked out in cancer. Which genes and proteins control these functions? Genes that cause cancer are called oncogenes. The normal forms of these genes are called proto­oncogenes. Researchers have identified a number of proto­oncogenes. Cyclin D1 is one; another is ras, short for "rat sarcoma," so named due to its initial discovery in rodents. The ras gene codes for a G protein that relays a signal from a growth factor outside the cell to begin a cascade that ends with the synthesis of a protein that stimulates the cell cycle. As in cyclin D1 protein, an abundance of ras protein pushes the cell towards proliferation. About 30% of human cancers display mutations in the ras gene.

Oncogenes such as ras cause cells to proliferate because their protein products stimulate cell division. Other genes involved in cancer inhibit cell division. How is this possible? When genes that normally halt cell division or induce apoptosis (programmed cell death) do not do their jobs, cell division becomes uncontrolled. These genes are called tumor suppressor genes, not oncogenes. The gene most frequently altered in human cancers is a tumor suppressor gene called p53, which is mutated in more than half of human cancers (Figure 11).

Figure 11: p53, the most frequently mutated gene in human cancers. Normally, p53 pauses cell cycle progression while DNA is repaired or induces apoptosis (cell death). When p53 http://www.nature.com/principles/ebooks/principles­of­biology­104015/29145058/3 6/8 1/20/2015 Cell Cycle Control | Principles of Biology from Nature Education

does not work properly, cell cycle progression can proceed unchecked.

© 2011 Nature Education All rights reserved. Transcript

How are the functions of oncogenes and tumor suppressor genes altered? Three main events can change how genes are expressed: the number of copies of the gene in one cell changes, the gene's location changes, or a mutation develops within either the gene or its control element and is not corrected. More copies of a gene results in more of its protein product, while gene deletion eliminates the gene's product. A location change can put the gene under different controls that either encourage or suppress its transcription. Transcriptional control elements can also be disrupted by mutations. Mutations within the gene can lead to malformation and incorrect function of the protein product. In many tumors, scientists have found that one copy of p53 has been deleted from the cell, and the other copy has a mutation in at least one nucleotide that changes at least one amino acid in the protein product.

Future perspectives. Cell cycle regulation as it relates to cancer is an active area of research. Why does p53 sometimes induce apoptosis and other times arrest the cell cycle? Can mutated p53 be corrected so that it works again? Could viruses be used to insert the p53 gene into cells that lack functional p53? Researchers are studying all of these questions. Can you think of any other ways our knowledge about p53 could be used to design novel cancer therapies?

Another gene currently being researched has the opposite effect of p53. The gene inhibits apoptosis and is commonly expressed in tumors but not in normal tissues. Cancers expressing this gene are more likely to progress aggressively, reducing patient survival. Researchers in Copenhagen, Denmark, have investigated whether it is possible to generate a sustained immune response specific to survivin, so as to create a vaccine against cancers. In March 2011, a research team at Discovery Research and Pharmaceutical Development in Washington state and Kyoto University in Japan reported successfully using RNA interference to block survivin expression in mice with bladder cancer. RNA interference is a naturally occurring method for controlling gene expression, and researchers have learned to use it to target specific genes. Researchers at Kinki University in Osaka, Japan reported using RNA interference to block survivin expression and increase the efficacy of a cancer drug in causing apoptosis of breast cancer cells in vitro.

The mechanisms underlying cell cycle regulation are numerous and complex. An amazing amount of the time, cells divide accurately to create identical daughter cells and stop proliferating when damage occurs or conditions are unfavorable for growth. Understanding how internal and external signals regulate cell division may help us learn how to correct the process when it goes awry or target cells that have begun uncontrolled proliferation.

IN THIS MODULE

Overview of Cell Cycle Regulation Maturation­promoting Factor Was the First Complex Identified that Controls the Cell Cycle There Are Many Cyclins in Cells Summary Test Your Knowledge

http://www.nature.com/principles/ebooks/principles­of­biology­104015/29145058/3 7/8 1/20/2015 Cell Cycle Control | Principles of Biology from Nature Education

WHY DOES THIS TOPIC MATTER?

Cancer: What's Old Is New Again Is cancer ancient, or is it largely a product of modern times? Can cutting­edge research lead to prevention and treatment strategies that could make cancer obsolete?

Stem Cells Stem cells are powerful tools in biology and medicine. What can scientists do with these cells and their incredible potential?

PRIMARY LITERATURE

The memory of iPS cells Incomplete DNA methylation underlies a transcriptional memory of somatic cells in human iPS cells. View | Download

Genetically­matched iPS cells more immunogenic than ES cells Immunogenicity of induced pluripotent stem cells. View | Download

Adaptor proteins regulate cell signaling Structural basis for regulation of the Crk signaling protein by a proline switch. View | Download

The role of cyclin D1 in DNA repair linked to cancer growth A function for cyclin D1 in DNA repair uncovered by protein interactome analyses in human cancers. View | Download

SCIENCE ON THE WEB

Follow the Cell Cycle An animated diagram of the cell cycle

The Nitty­gritty of Cell Cycle Control Read a Scitable article on cell cycle control and cancer

Targeted Therapy Watch a lecture on Gleevec, a cancer therapeutic targeting tyrosine receptor kinases

Discover more about p53 Play this interactive to learn about "The Guardian of the Genome"

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contents Principles of Biology

33 Cell Cycle Control Summary

OBJECTIVE Describe the molecular system that regulates progression through the cell cycle. At various checkpoints in the cell cycle, a cell may stop progressing because necessary steps are unfinished or conditions outside the cell are unfavorable for proliferation. These check points are the G1, G2 and M checkpoints in the G1, G2 and M phases of the cell cycle. A cell that stops progressing may enter G0 phase, die through apoptosis, or pause temporarily while repairs are made or some part of the cell division process catches up with the rest of it. Cyclin­ dependent kinases are active in cell cycle regulation. During certain parts of the cell cycle, the kinases complex with cyclin, and the Cdk­cyclin complexes activate enzymes through phosphorylation. They contribute to chromosome condensation, cell membrane breakdown, and mitotic spindle assembly at the beginning of mitosis, and they play a role in chromosome separation and cytokinesis later on. Other proteins also contribute to cell cycle regulation by activating enzymes at particular checkpoints.

OBJECTIVE Describe how cell cycle control mechanisms respond to internal and external signals. As well as reacting to internal cues, the cell cycle reacts to external cues. Cells will not divide if the environment lacks crucial nutrients, and most animal cells will not divide without specific growth factors being present in the environment. Extracellular signaling molecules can initiate a cascade reaction by binding to a transmembrane receptor. Receptor tyrosine kinases, such as the PDGF receptor, are one type of receptor important in cell signaling pathways. Normal animal cells usually exhibit density­dependent inhibition and anchorage dependence, meaning they will not proliferate if crowded or unattached to a surface.

OBJECTIVE Explain how cancers result from breakdowns in cell cycle control. Cancer is caused by breakdowns in cell cycle control. Its relevance to cancer makes cell cycle control an active area of scientific research. Oncogenes such as ras stimulate uncontrolled proliferation, whereas tumor suppressor genes such as p53 inhibit cell cycle progression. In many cases, mutations accumulate over time before the cancer becomes malignant, or acquires the ability to spread to other tissues.

Key Terms

anchorage dependence Most animal cells must be attached to a surface or tissue to divide.

benign tumor Abnormal tissue growth that does not spread to other parts of the body.

cell cycle control system System which controls which phase a cell is in.

checkpoint One of many specific timepoints in the cell cycle that are transitions between phases; a timepoint when the cycle can be halted or allowed to progress.

cyclin Protein whose concentration varies cyclically.

cyclin­dependent kinase (Cdk) A type of protein involved in cell cycle regulation; exists in many subforms, each with a different function.

density­dependent inhibition Cell division normally stops if the cells are crowded together.

G0 phase Extended, non­dividing stage in cells that divide infrequently.

growth factor Protein which stimulates cell division.

malignant tumor A tumor whose uncontrolled growth spreads to neighboring tissues and throughout the body, producing metastases; a type of cell mass that is distinguished from a benign tumor which does not spread or show uncontrolled growth.

metastasis Process by which malignant tumors spread to other parts of the body.

oncogene A gene that triggers a cell to divide uncontrollably, regardless of proper signaling; sometimes a mutated form of a proto­oncogene.

proto­oncogene A normal form of an oncogene; stimulates cell division, regulates cell differentiation, and inhibits cell death.

tumor suppressor gene A gene that normally halts cell division or induces apoptosis. http://www.nature.com/principles/ebooks/principles­of­biology­104015/29145058/4 1/2 1/20/2015 Summary of Cell Cycle Control | Principles of Biology from Nature Education

IN THIS MODULE

Overview of Cell Cycle Regulation Maturation­promoting Factor Was the First Complex Identified that Controls the Cell Cycle There Are Many Cyclins in Cells Summary Test Your Knowledge

WHY DOES THIS TOPIC MATTER?

Cancer: What's Old Is New Again Is cancer ancient, or is it largely a product of modern times? Can cutting­edge research lead to prevention and treatment strategies that could make cancer obsolete?

Stem Cells Stem cells are powerful tools in biology and medicine. What can scientists do with these cells and their incredible potential?

PRIMARY LITERATURE

The memory of iPS cells Incomplete DNA methylation underlies a transcriptional memory of somatic cells in human iPS cells. View | Download

Genetically­matched iPS cells more immunogenic than ES cells Immunogenicity of induced pluripotent stem cells. View | Download

Adaptor proteins regulate cell signaling Structural basis for regulation of the Crk signaling protein by a proline switch. View | Download

The role of cyclin D1 in DNA repair linked to cancer growth A function for cyclin D1 in DNA repair uncovered by protein interactome analyses in human cancers. View | Download

SCIENCE ON THE WEB

Follow the Cell Cycle An animated diagram of the cell cycle

The Nitty­gritty of Cell Cycle Control Read a Scitable article on cell cycle control and cancer

Targeted Therapy Watch a lecture on Gleevec, a cancer therapeutic targeting tyrosine receptor kinases

Discover more about p53 Play this interactive to learn about "The Guardian of the Genome"

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contents Principles of Biology

33 Cell Cycle Control

IN THIS MODULE

Overview of Cell Cycle Regulation Test Your Knowledge Maturation­promoting Factor Was the First Complex Identified that Controls the Cell Cycle 1. Which cell cycle phase are most cells of the human body in most of the time? There Are Many Cyclins in Cells

G0 Summary G1 Test Your Knowledge G 2 S M WHY DOES THIS TOPIC MATTER?

Cancer: What's Old Is New Again Is cancer ancient, or is it largely a 2. What is the basic function of the various types of kinases active in the cell cycle control system? product of modern times? Can cutting­edge research lead to prevention to phosphorylate proteins and treatment strategies that could make to prevent oxidation cancer obsolete? to synthesize vitamin D Stem Cells to transcribe tumor suppressor genes Stem cells are powerful tools in to control mitotic spindle assembly biology and medicine. What can scientists do with these cells and their incredible potential?

3. Which process may result in overexpression of an oncogene? PRIMARY LITERATURE

The cell acquires extra copies of the gene. The memory of iPS cells The gene is translocated to another part of the genome. Incomplete DNA methylation underlies a A mutation develops within the gene. transcriptional memory of somatic cells in A mutation occurs within the gene’s control element. human iPS cells. All answers are correct. View | Download Genetically­matched iPS cells more immunogenic than ES cells Immunogenicity of induced pluripotent stem 4. Which of the following statements regarding anchorage dependence is true? cells. View | Download Cells will stop dividing if the environment doesn’t contain the proper growth factors. Anchored cells don’t move up through tissues to replace old cells. Adaptor proteins regulate cell signaling Most animal cells will not proliferate if they have no surface to adhere to. Structural basis for regulation of the Crk Anchorage dependence prevents cells from transforming into cancer cells. signaling protein by a proline switch. Cells will stop dividing if they are crowded. View | Download

The role of cyclin D1 in DNA repair linked to cancer growth A function for cyclin D1 in DNA repair 5. Why is the G1 checkpoint particularly important in mammalian cells? uncovered by protein interactome analyses A cell that passes the G checkpoint usually begins the process of cell division. in human cancers. 1 View | Download Cells that do not pass this checkpoint go into M. The G1 checkpoint immediately precedes mitosis. If one cell's nucleus is in G1 and the other is in S, when the nuclei are fused, the new cell (a fusion SCIENCE ON THE WEB product of the two cells) will go immediately into G1. Follow the Cell Cycle The G1 phase is particularly lengthy and energy consuming. An animated diagram of the cell cycle

The Nitty­gritty of Cell Cycle Control Read a Scitable article on cell cycle control 6. Why is deletion of p53 genes damaging to an organism? and cancer

p53 genes encode kinases necessary for cell cycle control. Targeted Therapy Without p53, cells stop proliferating and enter G . Watch a lecture on Gleevec, a cancer 0 therapeutic targeting tyrosine receptor The p53 protein pauses the cell cycle for repairs when necessary. kinases p53 is on the Y chromosome. The p53 protein promotes cell proliferation. Discover more about p53 Play this interactive to learn about "The Guardian of the Genome"

7. A mutation in which of the following proteins would be predicted to have the most similar effect as a mutation in Plk?

cyclin B Cdk1 tubulin cyclin D1 Aurora kinase

Submit

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