{"id":2402,"date":"2016-05-24T20:49:02","date_gmt":"2016-05-24T20:49:02","guid":{"rendered":"https:\/\/courses.lumenlearning.com\/biologyxwaymakerxmaster\/?post_type=chapter&#038;p=2402"},"modified":"2017-08-08T15:13:12","modified_gmt":"2017-08-08T15:13:12","slug":"cell-cycle-checkpoints","status":"publish","type":"chapter","link":"https:\/\/courses.lumenlearning.com\/suny-wmopen-biology1\/chapter\/cell-cycle-checkpoints\/","title":{"raw":"Cell Cycle Checkpoints","rendered":"Cell Cycle Checkpoints"},"content":{"raw":"<h2>Identify and explain the important checkpoints that a cell passes through during the cell cycle<\/h2>\r\nAs we just learned, the cell cycle is a fairly complicated process.\u00a0In order to make sure everything goes right, there are checkpoints in the cycle. Let's learn about these and how they help control the cell cycle.\r\n<div class=\"textbox learning-objectives\">\r\n<h3>Learning Objectives<\/h3>\r\n<ul>\r\n \t<li>Identify important checkpoints in cell division<\/li>\r\n \t<li>Explain how errors in cell division are related to cancer<\/li>\r\n<\/ul>\r\n<\/div>\r\nThe 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 cells, and to an entire human lifetime spent in G<sub>0<\/sub> by specialized cells, such as cortical neurons 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 (outside the body under optimal growing conditions), the length of the cycle is about 24 hours. In rapidly dividing human cells with a 24-hour cell cycle, the G<sub>1<\/sub> phase lasts approximately nine hours, the S phase lasts 10 hours, the G<sub>2<\/sub> 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.\r\n<h2>Regulation of the Cell Cycle by External Events<\/h2>\r\nBoth 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 sweeping as the release of growth-promoting hormones, such as human growth hormone (HGH). A lack of HGH can inhibit cell division, resulting in dwarfism, whereas too much HGH can result in gigantism. Crowding of cells can also inhibit 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.\r\n\r\nWhatever the source of the message, the cell receives the signal, and a series of events within the cell allows it to proceed into interphase. Moving forward from this initiation point, every parameter required during each cell cycle phase must be met or the cycle cannot progress.\r\n<h2>Regulation at Internal Checkpoints<\/h2>\r\nIt is essential that the daughter cells produced be exact duplicates of the parent cell. Mistakes in the duplication or distribution of the chromosomes lead to mutations that may be passed forward to every new cell produced from an abnormal cell. To prevent a compromised cell from continuing to divide, there are internal control mechanisms that operate at three main cell cycle checkpoints. A checkpoint is one of several points in the eukaryotic cell cycle at which the progression of a cell to the next stage in the cycle can be halted until conditions are favorable. These checkpoints occur near the end of G<sub>1<\/sub>, at the G<sub>2<\/sub>\/M transition, and during metaphase (Figure\u00a01).\r\n\r\n[caption id=\"attachment_1807\" align=\"aligncenter\" width=\"800\"]<img class=\"size-full wp-image-1807\" src=\"https:\/\/s3-us-west-2.amazonaws.com\/courses-images\/wp-content\/uploads\/sites\/110\/2016\/05\/03210034\/Figure_10_03_01.jpg\" alt=\"This illustration shows the three major checkpoints of the cell cycle: G_{1}, G_{2}, and M.\" width=\"800\" height=\"611\" \/> Figure\u00a01. The cell cycle is controlled at three checkpoints. The integrity of the DNA is assessed at the G<sub>1<\/sub> checkpoint. Proper chromosome duplication is assessed at the G<sub>2<\/sub> checkpoint. Attachment of each kinetochore to a spindle fiber is assessed at the M checkpoint.[\/caption]\r\n<h3>The G<sub>1<\/sub> Checkpoint<\/h3>\r\nThe G<sub>1<\/sub> checkpoint determines whether all conditions are favorable for cell division to proceed. The G<sub>1<\/sub> checkpoint, also called the restriction point (in yeast), is a point at which the cell irreversibly commits to the cell division process. External influences, such as growth factors, play a large role in carrying the cell past the G<sub>1<\/sub> checkpoint. In addition to adequate reserves and cell size, there is a check for genomic DNA damage at the G<sub>1<\/sub> 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 G<sub>0<\/sub> and await further signals when conditions improve.\r\n<h3>The G<sub>2<\/sub> Checkpoint<\/h3>\r\nThe G<sub>2<\/sub> checkpoint bars entry into the mitotic phase if certain conditions are not met. As at the G<sub>1<\/sub> checkpoint, cell size and protein reserves are assessed. However, the most important role of the G<sub>2<\/sub> 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 halted, and the cell attempts to either complete DNA replication or repair the damaged DNA.\r\n<h3>The M Checkpoint<\/h3>\r\nThe M checkpoint occurs near the end of the metaphase stage of karyokinesis. The M checkpoint is also known as the spindle checkpoint, because it determines whether all the sister chromatids are correctly attached to the spindle microtubules. Because the separation of the sister chromatids during anaphase is an irreversible step, the cycle will not proceed until the kinetochores of each pair of sister chromatids are firmly anchored to at least two spindle fibers arising from opposite poles of the cell.\r\n<div class=\"textbox shaded\">Watch what occurs at the G<sub>1<\/sub>, G<sub>2<\/sub>, and M checkpoints by <a href=\"http:\/\/outreach.mcb.harvard.edu\/animations\/checkpoints.swf\" target=\"_blank\" rel=\"noopener\">downloading this animation of the cell cycle<\/a>.<\/div>\r\n<h2>Regulator Molecules of the Cell Cycle<\/h2>\r\nIn addition to the internally controlled checkpoints, there are two groups of intracellular molecules that regulate the cell cycle. These regulatory molecules either promote progress of the cell to the next phase (positive regulation) or halt the cycle (negative regulation). Regulator molecules may act individually, or they can influence the activity or production of other regulatory proteins. Therefore, the failure of a single regulator may have almost no effect on the cell cycle, especially if more than one mechanism controls the same event. Conversely, the effect of a deficient or non-functioning regulator can be wide-ranging and possibly fatal to the cell if multiple processes are affected.\r\n<h3>Positive Regulation of the Cell Cycle<\/h3>\r\nTwo groups of proteins, called cyclins and cyclin-dependent kinases (Cdks), are responsible for the progress of the cell through the various checkpoints. The levels of the four cyclin proteins fluctuate throughout the cell cycle in a predictable pattern (Figure\u00a02). 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.\r\n\r\n[caption id=\"attachment_1669\" align=\"aligncenter\" width=\"544\"]<img class=\"wp-image-1669 size-full\" src=\"https:\/\/s3-us-west-2.amazonaws.com\/courses-images\/wp-content\/uploads\/sites\/110\/2016\/05\/02235459\/Figure_10_03_02.jpg\" alt=\"This graph shows the concentrations of different cyclin proteins during various phases of the cell cycle. Cyclin D concentrations increase in G_{1} and decrease at the end of mitosis. Cyclin E levels rise during G_{1} and fall during S phase. Cyclin A levels rise during S phase and fall during mitosis. Cyclin B levels rise in S phase and fall during mitosis.\" width=\"544\" height=\"329\" \/> Figure\u00a02. The concentrations of cyclin proteins change throughout the cell cycle. There is a direct correlation between cyclin accumulation and the three major cell cycle checkpoints. Also note the sharp decline of cyclin levels following each checkpoint (the transition between phases of the cell cycle), as cyclin is degraded by cytoplasmic enzymes. (credit: modification of work by \"WikiMiMa\"\/Wikimedia Commons)[\/caption]\r\n\r\nCyclins regulate the cell cycle only when they are tightly bound to Cdks. To be fully active, the Cdk\/cyclin complex must also be phosphorylated in specific locations. Like all kinases, Cdks are enzymes (kinases) that phosphorylate other proteins. Phosphorylation activates the protein by changing its shape. The proteins phosphorylated by Cdks are involved in advancing the cell to the next phase (Figure\u00a03). The levels of Cdk proteins are relatively stable throughout the cell cycle; however, the concentrations of cyclin fluctuate and determine when Cdk\/cyclin complexes form. The different cyclins and Cdks bind at specific points in the cell cycle and thus regulate different checkpoints.\r\n\r\n[caption id=\"attachment_1808\" align=\"aligncenter\" width=\"544\"]<img class=\"size-full wp-image-1808\" src=\"https:\/\/s3-us-west-2.amazonaws.com\/courses-images\/wp-content\/uploads\/sites\/110\/2016\/05\/03210900\/Figure_10_03_03_prev1.jpg\" alt=\"This illustration shows a cyclin protein binding to a Cdk. The cyclin\/Cdk complex is activated when a kinase phosphorylates it. The cyclin\/Cdk complex, in turn, phosphorylates other proteins, thus advancing the cell cycle.\" width=\"544\" height=\"1018\" \/> Figure\u00a03. Cyclin-dependent kinases (Cdks) are protein kinases that, when fully activated, can phosphorylate and thus activate other proteins that advance the cell cycle past a checkpoint. To become fully activated, a Cdk must bind to a cyclin protein and then be phosphorylated by another kinase.[\/caption]\r\n\r\nSince the cyclic fluctuations of cyclin levels are based on the timing of the cell cycle and not on specific events, regulation of the cell cycle usually occurs by either the Cdk molecules alone or the Cdk\/cyclin complexes. Without a specific concentration of fully activated cyclin\/Cdk complexes, the cell cycle cannot proceed through the checkpoints.\r\n\r\nAlthough the cyclins are the main regulatory molecules that determine the forward momentum of the cell cycle, there are several other mechanisms that fine-tune the progress of the cycle with negative, rather than positive, effects. These mechanisms essentially block the progression of the cell cycle until problematic conditions are resolved. Molecules that prevent the full activation of Cdks are called Cdk inhibitors. Many of these inhibitor molecules directly or indirectly monitor a particular cell cycle event. The block placed on Cdks by inhibitor molecules will not be removed until the specific event that the inhibitor monitors is completed.\r\n<h3>Negative Regulation of the Cell Cycle<\/h3>\r\nThe second group of cell cycle regulatory molecules are negative regulators. Negative regulators halt the cell cycle. Remember that in positive regulation, active molecules cause the cycle to progress.\r\n\r\nThe best understood negative regulatory molecules are retinoblastoma protein (Rb), p53, and p21. Retinoblastoma proteins are a group of tumor-suppressor proteins common in many cells. The 53 and 21 designations refer to the functional molecular masses of the proteins (p) in kilodaltons. Much of what is known about cell cycle regulation comes from research conducted with cells that have lost regulatory control. All three of these regulatory proteins were discovered to be damaged or non-functional in cells that had begun to replicate uncontrollably (became cancerous). In each case, the main cause of the unchecked progress through the cell cycle was a faulty copy of the regulatory protein.\r\n\r\nRb, p53, and p21 act primarily at the G<sub>1<\/sub> checkpoint. p53 is a multi-functional protein that has a major impact on the commitment of a cell to division because it acts when there is damaged DNA in cells that are undergoing the preparatory processes during G<sub>1<\/sub>. If damaged DNA is detected, p53 halts the cell cycle and recruits enzymes to repair the DNA. If the DNA cannot be repaired, p53 can trigger apoptosis, or cell suicide, to prevent the duplication of damaged chromosomes. As p53 levels rise, the production of p21 is triggered. p21 enforces the halt in the cycle dictated by p53 by binding to and inhibiting the activity of the Cdk\/cyclin complexes. As a cell is exposed to more stress, higher levels of p53 and p21 accumulate, making it less likely that the cell will move into the S phase.\r\n\r\nRb exerts its regulatory influence on other positive regulator proteins. Chiefly, Rb monitors cell size. In the active, dephosphorylated state, Rb binds to proteins called transcription factors, most commonly, E2F (Figure\u00a04). Transcription factors \"turn on\" specific genes, allowing the production of proteins encoded by that gene. When Rb is bound to E2F, production of proteins necessary for the G<sub>1<\/sub>\/S transition is blocked. As the cell increases in size, Rb is slowly phosphorylated until it becomes inactivated. Rb releases E2F, which can now turn on the gene that produces the transition protein, and this particular block is removed. For the cell to move past each of the checkpoints, all positive regulators must be \"turned on,\" and all negative regulators must be \"turned off.\"\r\n<div class=\"textbox exercises\">\r\n<h3>Practice Question<\/h3>\r\n[caption id=\"attachment_1809\" align=\"aligncenter\" width=\"728\"]<img class=\"size-full wp-image-1809\" src=\"https:\/\/s3-us-west-2.amazonaws.com\/courses-images\/wp-content\/uploads\/sites\/110\/2016\/05\/03210952\/Figure_10_03_041.png\" alt=\"This illustration shows the regulation of the cell cycle by the Rb protein. Unphosphorylated Rb binds the transcription factor E2F. E2F cannot bind the DNA, and transcription is blocked. Cell growth triggers the phosphorylation of Rb. Phosphorylated Rb releases E2F, which binds the DNA and turns on gene expression, thus advancing the cell cycle.\" width=\"728\" height=\"476\" \/> Figure\u00a04. Rb halts the cell cycle and releases its hold in response to cell growth.[\/caption]\r\n\r\nRb and other proteins that negatively regulate the cell cycle are sometimes called tumor suppressors. Why do you think the name tumor suppressor might be appropriate for these proteins?\r\n\r\n[practice-area rows=\"2\"][\/practice-area]\r\n[reveal-answer q=\"518676\"]<strong>Show Answer<\/strong>[\/reveal-answer]\r\n[hidden-answer a=\"518676\"]Rb and other negative regulatory proteins control cell division and therefore prevent the formation of tumors. Mutations that prevent these proteins from carrying out their function can result in cancer.[\/hidden-answer]\r\n\r\n<\/div>\r\n<h2>Cancer and the Cell Cycle<\/h2>\r\nCancer comprises many different diseases caused by a common mechanism: uncontrolled cell growth. Despite the redundancy and overlapping levels of cell cycle control, errors do occur. One of the critical processes monitored by the cell cycle checkpoint surveillance mechanism is the proper replication of DNA during the S phase. Even when all of the cell cycle controls are fully functional, a small percentage of replication errors (mutations) will be passed on to the daughter cells. If changes to the DNA nucleotide sequence occur within a coding portion of a gene and are not corrected, a gene mutation results. All cancers start when a gene mutation gives rise to a faulty protein that plays a key role in cell reproduction. The change in the cell that results from the malformed protein may be minor: perhaps a slight delay in the binding of Cdk to cyclin or an Rb protein that detaches from its target DNA while still phosphorylated. Even minor mistakes, however, may allow subsequent mistakes to occur more readily. Over and over, small uncorrected errors are passed from the parent cell to the daughter cells and amplified as each generation produces more non-functional proteins from uncorrected DNA damage. Eventually, the pace of the cell cycle speeds up as the effectiveness of the control and repair mechanisms decreases. Uncontrolled growth of the mutated cells outpaces the growth of normal cells in the area, and a tumor (~<em>oma<\/em>) can result.\r\n<h3>Proto-oncogenes<\/h3>\r\nThe genes that code for the positive cell cycle regulators are called\u00a0<strong>proto-oncogenes<\/strong>. Proto-oncogenes are normal genes that, when mutated in certain ways, become <strong>oncogenes<\/strong>, 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 propagated and the damage is minimal. Occasionally, however, a gene mutation causes a change that increases the activity of a positive regulator. For example, a mutation that allows Cdk to be activated without being partnered with cyclin could push the cell cycle past a checkpoint before all of the required conditions are met. If the resulting daughter cells are too damaged to undergo further cell divisions, the mutation would not be propagated and no harm would come to the organism. However, if the atypical daughter cells are able to undergo further cell divisions, subsequent generations of cells will probably accumulate even more mutations, some possibly in additional genes that regulate the cell cycle.\r\n\r\nThe Cdk gene in the above example is only one of many genes that are considered proto-oncogenes. In addition to the cell cycle regulatory proteins, any protein that influences the cycle can be altered in such a way as to override cell cycle checkpoints. An oncogene is any gene that, when altered, leads to an increase in the rate of cell cycle progression.\r\n<h3>Tumor Suppressor Genes<\/h3>\r\nLike proto-oncogenes, many of the negative cell cycle regulatory proteins were discovered in cells that had become cancerous.\u00a0<strong>Tumor suppressor genes<\/strong> 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, 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 halt 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.\r\n\r\nMutated p53 genes have been identified in more than one-half of all human tumor cells. This discovery is not surprising in light of the multiple roles that the p53 protein plays at the G<sub>1<\/sub> checkpoint. A cell with a faulty p53 may fail to detect errors present in the genomic DNA (Figure 5). 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). The damaged version of p53 found in cancer cells, however, cannot trigger apoptosis.\r\n\r\n[caption id=\"attachment_1812\" align=\"aligncenter\" width=\"725\"]<img class=\"size-full wp-image-1812\" src=\"https:\/\/s3-us-west-2.amazonaws.com\/courses-images\/wp-content\/uploads\/sites\/110\/2016\/05\/03211301\/Figure_10_04_011.png\" alt=\"Part a: This illustration shows cell cycle regulation by normal p53, which arrests the cell cycle in response to DNA damage, cell cycle abnormalities, or hypoxia. Once the damage is repaired, the cell cycle restarts. If the damage cannot be repaired, apoptosis (programmed cell death) occurs. Part b: Mutated p53 does not arrest the cell cycle in response to cellular damage. As a result, the cell cycle continues, and the cell may become cancerous.\" width=\"725\" height=\"598\" \/> Figure 5. The role of normal p53 is to monitor DNA and the supply of oxygen (hypoxia is a condition of reduced oxygen supply). If damage is detected, p53 triggers repair mechanisms. If repairs are unsuccessful, p53 signals apoptosis. A cell with an abnormal p53 protein cannot repair damaged DNA and thus cannot signal apoptosis. Cells with abnormal p53 can become cancerous. (credit: modification of work by Thierry Soussi)[\/caption]\r\n\r\nThe 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 Cdk activation. Essentially, without a fully functional p53, the G<sub>1<\/sub> checkpoint is severely compromised and the cell proceeds directly from G<sub>1<\/sub> 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 non-optimal conditions under which the parent cell reproduced, it is likely that the daughter cells will have acquired 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.\r\n<div class=\"textbox shaded\">\r\n\r\nThis video reviews the ways that cancer is a by-product of broken DNA replication:\r\n\r\nhttps:\/\/youtu.be\/RZhL7LDPk8w\r\n\r\n<\/div>\r\n<div class=\"textbox learning-objectives\">\r\n<h3>In Summary: Cell Cycle Checkpoints<\/h3>\r\nEach 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 G<sub>1<\/sub>, a second at the G<sub>2<\/sub>\/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.\r\n\r\nCancer 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 monitoring system 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).\r\n\r\n<\/div>\r\n<h2><strong>Check Your Understanding<\/strong><\/h2>\r\nAnswer the question(s) below to see how well you understand the topics covered in the previous section. This short quiz does\u00a0<strong>not<\/strong>\u00a0count toward your grade in the class, and you can retake it an unlimited number of times.\r\n\r\nUse this quiz to check your understanding and decide whether to (1) study the previous section further or (2) move on to the next section.\r\n\r\nhttps:\/\/assessments.lumenlearning.com\/assessments\/3351","rendered":"<h2>Identify and explain the important checkpoints that a cell passes through during the cell cycle<\/h2>\n<p>As we just learned, the cell cycle is a fairly complicated process.\u00a0In order to make sure everything goes right, there are checkpoints in the cycle. Let&#8217;s learn about these and how they help control the cell cycle.<\/p>\n<div class=\"textbox learning-objectives\">\n<h3>Learning Objectives<\/h3>\n<ul>\n<li>Identify important checkpoints in cell division<\/li>\n<li>Explain how errors in cell division are related to cancer<\/li>\n<\/ul>\n<\/div>\n<p>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 cells, and to an entire human lifetime spent in G<sub>0<\/sub> by specialized cells, such as cortical neurons 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 (outside the body under optimal growing conditions), the length of the cycle is about 24 hours. In rapidly dividing human cells with a 24-hour cell cycle, the G<sub>1<\/sub> phase lasts approximately nine hours, the S phase lasts 10 hours, the G<sub>2<\/sub> 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.<\/p>\n<h2>Regulation of the Cell Cycle by External Events<\/h2>\n<p>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 sweeping as the release of growth-promoting hormones, such as human growth hormone (HGH). A lack of HGH can inhibit cell division, resulting in dwarfism, whereas too much HGH can result in gigantism. Crowding of cells can also inhibit 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.<\/p>\n<p>Whatever the source of the message, the cell receives the signal, and a series of events within the cell allows it to proceed into interphase. Moving forward from this initiation point, every parameter required during each cell cycle phase must be met or the cycle cannot progress.<\/p>\n<h2>Regulation at Internal Checkpoints<\/h2>\n<p>It is essential that the daughter cells produced be exact duplicates of the parent cell. Mistakes in the duplication or distribution of the chromosomes lead to mutations that may be passed forward to every new cell produced from an abnormal cell. To prevent a compromised cell from continuing to divide, there are internal control mechanisms that operate at three main cell cycle checkpoints. A checkpoint is one of several points in the eukaryotic cell cycle at which the progression of a cell to the next stage in the cycle can be halted until conditions are favorable. These checkpoints occur near the end of G<sub>1<\/sub>, at the G<sub>2<\/sub>\/M transition, and during metaphase (Figure\u00a01).<\/p>\n<div id=\"attachment_1807\" style=\"width: 810px\" class=\"wp-caption aligncenter\"><img loading=\"lazy\" decoding=\"async\" aria-describedby=\"caption-attachment-1807\" class=\"size-full wp-image-1807\" src=\"https:\/\/s3-us-west-2.amazonaws.com\/courses-images\/wp-content\/uploads\/sites\/110\/2016\/05\/03210034\/Figure_10_03_01.jpg\" alt=\"This illustration shows the three major checkpoints of the cell cycle: G_{1}, G_{2}, and M.\" width=\"800\" height=\"611\" \/><\/p>\n<p id=\"caption-attachment-1807\" class=\"wp-caption-text\">Figure\u00a01. The cell cycle is controlled at three checkpoints. The integrity of the DNA is assessed at the G<sub>1<\/sub> checkpoint. Proper chromosome duplication is assessed at the G<sub>2<\/sub> checkpoint. Attachment of each kinetochore to a spindle fiber is assessed at the M checkpoint.<\/p>\n<\/div>\n<h3>The G<sub>1<\/sub> Checkpoint<\/h3>\n<p>The G<sub>1<\/sub> checkpoint determines whether all conditions are favorable for cell division to proceed. The G<sub>1<\/sub> checkpoint, also called the restriction point (in yeast), is a point at which the cell irreversibly commits to the cell division process. External influences, such as growth factors, play a large role in carrying the cell past the G<sub>1<\/sub> checkpoint. In addition to adequate reserves and cell size, there is a check for genomic DNA damage at the G<sub>1<\/sub> 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 G<sub>0<\/sub> and await further signals when conditions improve.<\/p>\n<h3>The G<sub>2<\/sub> Checkpoint<\/h3>\n<p>The G<sub>2<\/sub> checkpoint bars entry into the mitotic phase if certain conditions are not met. As at the G<sub>1<\/sub> checkpoint, cell size and protein reserves are assessed. However, the most important role of the G<sub>2<\/sub> 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 halted, and the cell attempts to either complete DNA replication or repair the damaged DNA.<\/p>\n<h3>The M Checkpoint<\/h3>\n<p>The M checkpoint occurs near the end of the metaphase stage of karyokinesis. The M checkpoint is also known as the spindle checkpoint, because it determines whether all the sister chromatids are correctly attached to the spindle microtubules. Because the separation of the sister chromatids during anaphase is an irreversible step, the cycle will not proceed until the kinetochores of each pair of sister chromatids are firmly anchored to at least two spindle fibers arising from opposite poles of the cell.<\/p>\n<div class=\"textbox shaded\">Watch what occurs at the G<sub>1<\/sub>, G<sub>2<\/sub>, and M checkpoints by <a href=\"http:\/\/outreach.mcb.harvard.edu\/animations\/checkpoints.swf\" target=\"_blank\" rel=\"noopener\">downloading this animation of the cell cycle<\/a>.<\/div>\n<h2>Regulator Molecules of the Cell Cycle<\/h2>\n<p>In addition to the internally controlled checkpoints, there are two groups of intracellular molecules that regulate the cell cycle. These regulatory molecules either promote progress of the cell to the next phase (positive regulation) or halt the cycle (negative regulation). Regulator molecules may act individually, or they can influence the activity or production of other regulatory proteins. Therefore, the failure of a single regulator may have almost no effect on the cell cycle, especially if more than one mechanism controls the same event. Conversely, the effect of a deficient or non-functioning regulator can be wide-ranging and possibly fatal to the cell if multiple processes are affected.<\/p>\n<h3>Positive Regulation of the Cell Cycle<\/h3>\n<p>Two groups of proteins, called cyclins and cyclin-dependent kinases (Cdks), are responsible for the progress of the cell through the various checkpoints. The levels of the four cyclin proteins fluctuate throughout the cell cycle in a predictable pattern (Figure\u00a02). 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.<\/p>\n<div id=\"attachment_1669\" style=\"width: 554px\" class=\"wp-caption aligncenter\"><img loading=\"lazy\" decoding=\"async\" aria-describedby=\"caption-attachment-1669\" class=\"wp-image-1669 size-full\" src=\"https:\/\/s3-us-west-2.amazonaws.com\/courses-images\/wp-content\/uploads\/sites\/110\/2016\/05\/02235459\/Figure_10_03_02.jpg\" alt=\"This graph shows the concentrations of different cyclin proteins during various phases of the cell cycle. Cyclin D concentrations increase in G_{1} and decrease at the end of mitosis. Cyclin E levels rise during G_{1} and fall during S phase. Cyclin A levels rise during S phase and fall during mitosis. Cyclin B levels rise in S phase and fall during mitosis.\" width=\"544\" height=\"329\" \/><\/p>\n<p id=\"caption-attachment-1669\" class=\"wp-caption-text\">Figure\u00a02. The concentrations of cyclin proteins change throughout the cell cycle. There is a direct correlation between cyclin accumulation and the three major cell cycle checkpoints. Also note the sharp decline of cyclin levels following each checkpoint (the transition between phases of the cell cycle), as cyclin is degraded by cytoplasmic enzymes. (credit: modification of work by &#8220;WikiMiMa&#8221;\/Wikimedia Commons)<\/p>\n<\/div>\n<p>Cyclins regulate the cell cycle only when they are tightly bound to Cdks. To be fully active, the Cdk\/cyclin complex must also be phosphorylated in specific locations. Like all kinases, Cdks are enzymes (kinases) that phosphorylate other proteins. Phosphorylation activates the protein by changing its shape. The proteins phosphorylated by Cdks are involved in advancing the cell to the next phase (Figure\u00a03). The levels of Cdk proteins are relatively stable throughout the cell cycle; however, the concentrations of cyclin fluctuate and determine when Cdk\/cyclin complexes form. The different cyclins and Cdks bind at specific points in the cell cycle and thus regulate different checkpoints.<\/p>\n<div id=\"attachment_1808\" style=\"width: 554px\" class=\"wp-caption aligncenter\"><img loading=\"lazy\" decoding=\"async\" aria-describedby=\"caption-attachment-1808\" class=\"size-full wp-image-1808\" src=\"https:\/\/s3-us-west-2.amazonaws.com\/courses-images\/wp-content\/uploads\/sites\/110\/2016\/05\/03210900\/Figure_10_03_03_prev1.jpg\" alt=\"This illustration shows a cyclin protein binding to a Cdk. The cyclin\/Cdk complex is activated when a kinase phosphorylates it. The cyclin\/Cdk complex, in turn, phosphorylates other proteins, thus advancing the cell cycle.\" width=\"544\" height=\"1018\" \/><\/p>\n<p id=\"caption-attachment-1808\" class=\"wp-caption-text\">Figure\u00a03. Cyclin-dependent kinases (Cdks) are protein kinases that, when fully activated, can phosphorylate and thus activate other proteins that advance the cell cycle past a checkpoint. To become fully activated, a Cdk must bind to a cyclin protein and then be phosphorylated by another kinase.<\/p>\n<\/div>\n<p>Since the cyclic fluctuations of cyclin levels are based on the timing of the cell cycle and not on specific events, regulation of the cell cycle usually occurs by either the Cdk molecules alone or the Cdk\/cyclin complexes. Without a specific concentration of fully activated cyclin\/Cdk complexes, the cell cycle cannot proceed through the checkpoints.<\/p>\n<p>Although the cyclins are the main regulatory molecules that determine the forward momentum of the cell cycle, there are several other mechanisms that fine-tune the progress of the cycle with negative, rather than positive, effects. These mechanisms essentially block the progression of the cell cycle until problematic conditions are resolved. Molecules that prevent the full activation of Cdks are called Cdk inhibitors. Many of these inhibitor molecules directly or indirectly monitor a particular cell cycle event. The block placed on Cdks by inhibitor molecules will not be removed until the specific event that the inhibitor monitors is completed.<\/p>\n<h3>Negative Regulation of the Cell Cycle<\/h3>\n<p>The second group of cell cycle regulatory molecules are negative regulators. Negative regulators halt the cell cycle. Remember that in positive regulation, active molecules cause the cycle to progress.<\/p>\n<p>The best understood negative regulatory molecules are retinoblastoma protein (Rb), p53, and p21. Retinoblastoma proteins are a group of tumor-suppressor proteins common in many cells. The 53 and 21 designations refer to the functional molecular masses of the proteins (p) in kilodaltons. Much of what is known about cell cycle regulation comes from research conducted with cells that have lost regulatory control. All three of these regulatory proteins were discovered to be damaged or non-functional in cells that had begun to replicate uncontrollably (became cancerous). In each case, the main cause of the unchecked progress through the cell cycle was a faulty copy of the regulatory protein.<\/p>\n<p>Rb, p53, and p21 act primarily at the G<sub>1<\/sub> checkpoint. p53 is a multi-functional protein that has a major impact on the commitment of a cell to division because it acts when there is damaged DNA in cells that are undergoing the preparatory processes during G<sub>1<\/sub>. If damaged DNA is detected, p53 halts the cell cycle and recruits enzymes to repair the DNA. If the DNA cannot be repaired, p53 can trigger apoptosis, or cell suicide, to prevent the duplication of damaged chromosomes. As p53 levels rise, the production of p21 is triggered. p21 enforces the halt in the cycle dictated by p53 by binding to and inhibiting the activity of the Cdk\/cyclin complexes. As a cell is exposed to more stress, higher levels of p53 and p21 accumulate, making it less likely that the cell will move into the S phase.<\/p>\n<p>Rb exerts its regulatory influence on other positive regulator proteins. Chiefly, Rb monitors cell size. In the active, dephosphorylated state, Rb binds to proteins called transcription factors, most commonly, E2F (Figure\u00a04). Transcription factors &#8220;turn on&#8221; specific genes, allowing the production of proteins encoded by that gene. When Rb is bound to E2F, production of proteins necessary for the G<sub>1<\/sub>\/S transition is blocked. As the cell increases in size, Rb is slowly phosphorylated until it becomes inactivated. Rb releases E2F, which can now turn on the gene that produces the transition protein, and this particular block is removed. For the cell to move past each of the checkpoints, all positive regulators must be &#8220;turned on,&#8221; and all negative regulators must be &#8220;turned off.&#8221;<\/p>\n<div class=\"textbox exercises\">\n<h3>Practice Question<\/h3>\n<div id=\"attachment_1809\" style=\"width: 738px\" class=\"wp-caption aligncenter\"><img loading=\"lazy\" decoding=\"async\" aria-describedby=\"caption-attachment-1809\" class=\"size-full wp-image-1809\" src=\"https:\/\/s3-us-west-2.amazonaws.com\/courses-images\/wp-content\/uploads\/sites\/110\/2016\/05\/03210952\/Figure_10_03_041.png\" alt=\"This illustration shows the regulation of the cell cycle by the Rb protein. Unphosphorylated Rb binds the transcription factor E2F. E2F cannot bind the DNA, and transcription is blocked. Cell growth triggers the phosphorylation of Rb. Phosphorylated Rb releases E2F, which binds the DNA and turns on gene expression, thus advancing the cell cycle.\" width=\"728\" height=\"476\" \/><\/p>\n<p id=\"caption-attachment-1809\" class=\"wp-caption-text\">Figure\u00a04. Rb halts the cell cycle and releases its hold in response to cell growth.<\/p>\n<\/div>\n<p>Rb and other proteins that negatively regulate the cell cycle are sometimes called tumor suppressors. Why do you think the name tumor suppressor might be appropriate for these proteins?<\/p>\n<p><textarea aria-label=\"Your Answer\" rows=\"2\"><\/textarea><\/p>\n<div class=\"qa-wrapper\" style=\"display: block\"><span class=\"show-answer collapsed\" style=\"cursor: pointer\" data-target=\"q518676\"><strong>Show Answer<\/strong><\/span><\/p>\n<div id=\"q518676\" class=\"hidden-answer\" style=\"display: none\">Rb and other negative regulatory proteins control cell division and therefore prevent the formation of tumors. Mutations that prevent these proteins from carrying out their function can result in cancer.<\/div>\n<\/div>\n<\/div>\n<h2>Cancer and the Cell Cycle<\/h2>\n<p>Cancer comprises many different diseases caused by a common mechanism: uncontrolled cell growth. Despite the redundancy and overlapping levels of cell cycle control, errors do occur. One of the critical processes monitored by the cell cycle checkpoint surveillance mechanism is the proper replication of DNA during the S phase. Even when all of the cell cycle controls are fully functional, a small percentage of replication errors (mutations) will be passed on to the daughter cells. If changes to the DNA nucleotide sequence occur within a coding portion of a gene and are not corrected, a gene mutation results. All cancers start when a gene mutation gives rise to a faulty protein that plays a key role in cell reproduction. The change in the cell that results from the malformed protein may be minor: perhaps a slight delay in the binding of Cdk to cyclin or an Rb protein that detaches from its target DNA while still phosphorylated. Even minor mistakes, however, may allow subsequent mistakes to occur more readily. Over and over, small uncorrected errors are passed from the parent cell to the daughter cells and amplified as each generation produces more non-functional proteins from uncorrected DNA damage. Eventually, the pace of the cell cycle speeds up as the effectiveness of the control and repair mechanisms decreases. Uncontrolled growth of the mutated cells outpaces the growth of normal cells in the area, and a tumor (~<em>oma<\/em>) can result.<\/p>\n<h3>Proto-oncogenes<\/h3>\n<p>The genes that code for the positive cell cycle regulators are called\u00a0<strong>proto-oncogenes<\/strong>. Proto-oncogenes are normal genes that, when mutated in certain ways, become <strong>oncogenes<\/strong>, 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 propagated and the damage is minimal. Occasionally, however, a gene mutation causes a change that increases the activity of a positive regulator. For example, a mutation that allows Cdk to be activated without being partnered with cyclin could push the cell cycle past a checkpoint before all of the required conditions are met. If the resulting daughter cells are too damaged to undergo further cell divisions, the mutation would not be propagated and no harm would come to the organism. However, if the atypical daughter cells are able to undergo further cell divisions, subsequent generations of cells will probably accumulate even more mutations, some possibly in additional genes that regulate the cell cycle.<\/p>\n<p>The Cdk gene in the above example is only one of many genes that are considered proto-oncogenes. In addition to the cell cycle regulatory proteins, any protein that influences the cycle can be altered in such a way as to override cell cycle checkpoints. An oncogene is any gene that, when altered, leads to an increase in the rate of cell cycle progression.<\/p>\n<h3>Tumor Suppressor Genes<\/h3>\n<p>Like proto-oncogenes, many of the negative cell cycle regulatory proteins were discovered in cells that had become cancerous.\u00a0<strong>Tumor suppressor genes<\/strong> 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, 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 halt 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.<\/p>\n<p>Mutated p53 genes have been identified in more than one-half of all human tumor cells. This discovery is not surprising in light of the multiple roles that the p53 protein plays at the G<sub>1<\/sub> checkpoint. A cell with a faulty p53 may fail to detect errors present in the genomic DNA (Figure 5). 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). The damaged version of p53 found in cancer cells, however, cannot trigger apoptosis.<\/p>\n<div id=\"attachment_1812\" style=\"width: 735px\" class=\"wp-caption aligncenter\"><img loading=\"lazy\" decoding=\"async\" aria-describedby=\"caption-attachment-1812\" class=\"size-full wp-image-1812\" src=\"https:\/\/s3-us-west-2.amazonaws.com\/courses-images\/wp-content\/uploads\/sites\/110\/2016\/05\/03211301\/Figure_10_04_011.png\" alt=\"Part a: This illustration shows cell cycle regulation by normal p53, which arrests the cell cycle in response to DNA damage, cell cycle abnormalities, or hypoxia. Once the damage is repaired, the cell cycle restarts. If the damage cannot be repaired, apoptosis (programmed cell death) occurs. Part b: Mutated p53 does not arrest the cell cycle in response to cellular damage. As a result, the cell cycle continues, and the cell may become cancerous.\" width=\"725\" height=\"598\" \/><\/p>\n<p id=\"caption-attachment-1812\" class=\"wp-caption-text\">Figure 5. The role of normal p53 is to monitor DNA and the supply of oxygen (hypoxia is a condition of reduced oxygen supply). If damage is detected, p53 triggers repair mechanisms. If repairs are unsuccessful, p53 signals apoptosis. A cell with an abnormal p53 protein cannot repair damaged DNA and thus cannot signal apoptosis. Cells with abnormal p53 can become cancerous. (credit: modification of work by Thierry Soussi)<\/p>\n<\/div>\n<p>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 Cdk activation. Essentially, without a fully functional p53, the G<sub>1<\/sub> checkpoint is severely compromised and the cell proceeds directly from G<sub>1<\/sub> 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 non-optimal conditions under which the parent cell reproduced, it is likely that the daughter cells will have acquired 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.<\/p>\n<div class=\"textbox shaded\">\n<p>This video reviews the ways that cancer is a by-product of broken DNA replication:<\/p>\n<p><iframe loading=\"lazy\" id=\"oembed-1\" title=\"Cancer | Cells | MCAT | Khan Academy\" width=\"500\" height=\"281\" src=\"https:\/\/www.youtube.com\/embed\/RZhL7LDPk8w?feature=oembed&#38;rel=0\" frameborder=\"0\" allowfullscreen=\"allowfullscreen\"><\/iframe><\/p>\n<\/div>\n<div class=\"textbox learning-objectives\">\n<h3>In Summary: Cell Cycle Checkpoints<\/h3>\n<p>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 G<sub>1<\/sub>, a second at the G<sub>2<\/sub>\/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.<\/p>\n<p>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 monitoring system 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).<\/p>\n<\/div>\n<h2><strong>Check Your Understanding<\/strong><\/h2>\n<p>Answer the question(s) below to see how well you understand the topics covered in the previous section. This short quiz does\u00a0<strong>not<\/strong>\u00a0count toward your grade in the class, and you can retake it an unlimited number of times.<\/p>\n<p>Use this quiz to check your understanding and decide whether to (1) study the previous section further or (2) move on to the next section.<\/p>\n<p>\t<iframe id=\"lumen_assessment_3351\" class=\"resizable\" src=\"https:\/\/assessments.lumenlearning.com\/assessments\/load?assessment_id=3351&#38;embed=1&#38;external_user_id=&#38;external_context_id=&#38;iframe_resize_id=lumen_assessment_3351\" frameborder=\"0\" style=\"border:none;width:100%;height:100%;min-height:400px;\"><br \/>\n\t<\/iframe><\/p>\n\n\t\t\t <section class=\"citations-section\" role=\"contentinfo\">\n\t\t\t <h3>Candela Citations<\/h3>\n\t\t\t\t\t <div>\n\t\t\t\t\t\t <div id=\"citation-list-2402\">\n\t\t\t\t\t\t\t <div class=\"licensing\"><div class=\"license-attribution-dropdown-subheading\">CC licensed content, Original<\/div><ul class=\"citation-list\"><li>Introduction to Cell Cycle Checkpoints. <strong>Authored by<\/strong>: Shelli Carter and Lumen Learning. <strong>Provided by<\/strong>: Lumen Learning. <strong>License<\/strong>: <em><a target=\"_blank\" rel=\"license\" href=\"https:\/\/creativecommons.org\/licenses\/by\/4.0\/\">CC BY: Attribution<\/a><\/em><\/li><\/ul><div class=\"license-attribution-dropdown-subheading\">CC licensed content, Shared previously<\/div><ul class=\"citation-list\"><li>Biology. <strong>Provided by<\/strong>: OpenStax CNX. <strong>Located at<\/strong>: <a target=\"_blank\" href=\"http:\/\/cnx.org\/contents\/185cbf87-c72e-48f5-b51e-f14f21b5eabd@10.8\">http:\/\/cnx.org\/contents\/185cbf87-c72e-48f5-b51e-f14f21b5eabd@10.8<\/a>. <strong>License<\/strong>: <em><a target=\"_blank\" rel=\"license\" href=\"https:\/\/creativecommons.org\/licenses\/by\/4.0\/\">CC BY: Attribution<\/a><\/em>. <strong>License Terms<\/strong>: Download for free at http:\/\/cnx.org\/contents\/185cbf87-c72e-48f5-b51e-f14f21b5eabd@10.8<\/li><li>Cell cycle regulation, cancer, and stem cells. <strong>Authored by<\/strong>: Sal Khan. <strong>Provided by<\/strong>: Khan Academy. <strong>Located at<\/strong>: <a target=\"_blank\" href=\"http:\/\/www.khanacademy.org\/video?v=RZhL7LDPk8w\">http:\/\/www.khanacademy.org\/video?v=RZhL7LDPk8w<\/a>. <strong>Project<\/strong>: Biology. <strong>License<\/strong>: <em><a target=\"_blank\" rel=\"license\" href=\"https:\/\/creativecommons.org\/licenses\/by-nc-sa\/4.0\/\">CC BY-NC-SA: Attribution-NonCommercial-ShareAlike<\/a><\/em><\/li><\/ul><\/div>\n\t\t\t\t\t\t <\/div>\n\t\t\t\t\t <\/div>\n\t\t\t <\/section>","protected":false},"author":17,"menu_order":4,"template":"","meta":{"_candela_citation":"[{\"type\":\"original\",\"description\":\"Introduction to Cell Cycle Checkpoints\",\"author\":\"Shelli Carter and Lumen Learning\",\"organization\":\"Lumen 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104ab2e9-948f-4591-aedf-e244dc352334","pb_show_title":"on","pb_short_title":"","pb_subtitle":"","pb_authors":[],"pb_section_license":""},"chapter-type":[],"contributor":[],"license":[],"class_list":["post-2402","chapter","type-chapter","status-publish","hentry"],"part":205,"_links":{"self":[{"href":"https:\/\/courses.lumenlearning.com\/suny-wmopen-biology1\/wp-json\/pressbooks\/v2\/chapters\/2402","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/courses.lumenlearning.com\/suny-wmopen-biology1\/wp-json\/pressbooks\/v2\/chapters"}],"about":[{"href":"https:\/\/courses.lumenlearning.com\/suny-wmopen-biology1\/wp-json\/wp\/v2\/types\/chapter"}],"author":[{"embeddable":true,"href":"https:\/\/courses.lumenlearning.com\/suny-wmopen-biology1\/wp-json\/wp\/v2\/users\/17"}],"version-history":[{"count":9,"href":"https:\/\/courses.lumenlearning.com\/suny-wmopen-biology1\/wp-json\/pressbooks\/v2\/chapters\/2402\/revisions"}],"predecessor-version":[{"id":4829,"href":"https:\/\/courses.lumenlearning.com\/suny-wmopen-biology1\/wp-json\/pressbooks\/v2\/chapters\/2402\/revisions\/4829"}],"part":[{"href":"https:\/\/courses.lumenlearning.com\/suny-wmopen-biology1\/wp-json\/pressbooks\/v2\/parts\/205"}],"metadata":[{"href":"https:\/\/courses.lumenlearning.com\/suny-wmopen-biology1\/wp-json\/pressbooks\/v2\/chapters\/2402\/metadata\/"}],"wp:attachment":[{"href":"https:\/\/courses.lumenlearning.com\/suny-wmopen-biology1\/wp-json\/wp\/v2\/media?parent=2402"}],"wp:term":[{"taxonomy":"chapter-type","embeddable":true,"href":"https:\/\/courses.lumenlearning.com\/suny-wmopen-biology1\/wp-json\/pressbooks\/v2\/chapter-type?post=2402"},{"taxonomy":"contributor","embeddable":true,"href":"https:\/\/courses.lumenlearning.com\/suny-wmopen-biology1\/wp-json\/wp\/v2\/contributor?post=2402"},{"taxonomy":"license","embeddable":true,"href":"https:\/\/courses.lumenlearning.com\/suny-wmopen-biology1\/wp-json\/wp\/v2\/license?post=2402"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}