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Biology for AP® Courses

10.3 Control of the Cell Cycle

Biology for AP® Courses10.3 Control of the Cell Cycle
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  1. Preface
  2. Unit 1
    1. 1 The Study of Life
      1. Introduction
      2. 1.1 The Science of Biology
      3. 1.2 Themes and Concepts of Biology
      4. Key Terms
      5. Chapter Summary
      6. Review Questions
      7. Critical Thinking Questions
      8. Test Prep for AP® Courses
    2. 2 The Chemical Foundation of Life
      1. Introduction
      2. 2.1 Atoms, Isotopes, Ions, and Molecules: The Building Blocks
      3. 2.2 Water
      4. 2.3 Carbon
      5. Key Terms
      6. Chapter Summary
      7. Review Questions
      8. Critical Thinking Questions
      9. Test Prep for AP® Courses
      10. Science Practice Challenge Questions
    3. 3 Biological Macromolecules
      1. Introduction
      2. 3.1 Synthesis of Biological Macromolecules
      3. 3.2 Carbohydrates
      4. 3.3 Lipids
      5. 3.4 Proteins
      6. 3.5 Nucleic Acids
      7. Key Terms
      8. Chapter Summary
      9. Review Questions
      10. Critical Thinking Questions
      11. Test Prep for AP® Courses
      12. Science Practice Challenge Questions
  3. Unit 2
    1. 4 Cell Structure
      1. Introduction
      2. 4.1 Studying Cells
      3. 4.2 Prokaryotic Cells
      4. 4.3 Eukaryotic Cells
      5. 4.4 The Endomembrane System and Proteins
      6. 4.5 Cytoskeleton
      7. 4.6 Connections between Cells and Cellular Activities
      8. Key Terms
      9. Chapter Summary
      10. Review Questions
      11. Critical Thinking Questions
      12. Test Prep for AP® Courses
      13. Science Practice Challenge Questions
    2. 5 Structure and Function of Plasma Membranes
      1. Introduction
      2. 5.1 Components and Structure
      3. 5.2 Passive Transport
      4. 5.3 Active Transport
      5. 5.4 Bulk Transport
      6. Key Terms
      7. Chapter Summary
      8. Review Questions
      9. Critical Thinking Questions
      10. Test Prep for AP® Courses
      11. Science Practice Challenge Questions
    3. 6 Metabolism
      1. Introduction
      2. 6.1 Energy and Metabolism
      3. 6.2 Potential, Kinetic, Free, and Activation Energy
      4. 6.3 The Laws of Thermodynamics
      5. 6.4 ATP: Adenosine Triphosphate
      6. 6.5 Enzymes
      7. Key Terms
      8. Chapter Summary
      9. Review Questions
      10. Critical Thinking Questions
      11. Test Prep for AP® Courses
      12. Science Practice Challenge Questions
    4. 7 Cellular Respiration
      1. Introduction
      2. 7.1 Energy in Living Systems
      3. 7.2 Glycolysis
      4. 7.3 Oxidation of Pyruvate and the Citric Acid Cycle
      5. 7.4 Oxidative Phosphorylation
      6. 7.5 Metabolism without Oxygen
      7. 7.6 Connections of Carbohydrate, Protein, and Lipid Metabolic Pathways
      8. 7.7 Regulation of Cellular Respiration
      9. Key Terms
      10. Chapter Summary
      11. Review Questions
      12. Critical Thinking Questions
      13. Test Prep for AP® Courses
      14. Science Practice Challenge Questions
    5. 8 Photosynthesis
      1. Introduction
      2. 8.1 Overview of Photosynthesis
      3. 8.2 The Light-Dependent Reaction of Photosynthesis
      4. 8.3 Using Light to Make Organic Molecules
      5. Key Terms
      6. Chapter Summary
      7. Review Questions
      8. Critical Thinking Questions
      9. Test Prep for AP® Courses
      10. Science Practice Challenge Questions
    6. 9 Cell Communication
      1. Introduction
      2. 9.1 Signaling Molecules and Cellular Receptors
      3. 9.2 Propagation of the Signal
      4. 9.3 Response to the Signal
      5. 9.4 Signaling in Single-Celled Organisms
      6. Key Terms
      7. Chapter Summary
      8. Review Questions
      9. Critical Thinking Questions
      10. Test Prep for AP® Courses
      11. Science Practice Challenge Questions
    7. 10 Cell Reproduction
      1. Introduction
      2. 10.1 Cell Division
      3. 10.2 The Cell Cycle
      4. 10.3 Control of the Cell Cycle
      5. 10.4 Cancer and the Cell Cycle
      6. 10.5 Prokaryotic Cell Division
      7. Key Terms
      8. Chapter Summary
      9. Review Questions
      10. Critical Thinking Questions
      11. Test Prep for AP® Courses
      12. Science Practice Challenge Questions
  4. Unit 3
    1. 11 Meiosis and Sexual Reproduction
      1. Introduction
      2. 11.1 The Process of Meiosis
      3. 11.2 Sexual Reproduction
      4. Key Terms
      5. Chapter Summary
      6. Review Questions
      7. Critical Thinking Questions
      8. Test Prep for AP® Courses
      9. Science Practice Challenge Questions
    2. 12 Mendel's Experiments and Heredity
      1. Introduction
      2. 12.1 Mendel’s Experiments and the Laws of Probability
      3. 12.2 Characteristics and Traits
      4. 12.3 Laws of Inheritance
      5. Key Terms
      6. Chapter Summary
      7. Review Questions
      8. Critical Thinking Questions
      9. Test Prep for AP® Courses
      10. Science Practice Challenge Questions
    3. 13 Modern Understandings of Inheritance
      1. Introduction
      2. 13.1 Chromosomal Theory and Genetic Linkages
      3. 13.2 Chromosomal Basis of Inherited Disorders
      4. Key Terms
      5. Chapter Summary
      6. Review Questions
      7. Critical Thinking Questions
      8. Test Prep for AP® Courses
      9. Science Practice Challenge Questions
    4. 14 DNA Structure and Function
      1. Introduction
      2. 14.1 Historical Basis of Modern Understanding
      3. 14.2 DNA Structure and Sequencing
      4. 14.3 Basics of DNA Replication
      5. 14.4 DNA Replication in Prokaryotes
      6. 14.5 DNA Replication in Eukaryotes
      7. 14.6 DNA Repair
      8. Key Terms
      9. Chapter Summary
      10. Review Questions
      11. Critical Thinking Questions
      12. Test Prep for AP® Courses
      13. Science Practice Challenge Questions
    5. 15 Genes and Proteins
      1. Introduction
      2. 15.1 The Genetic Code
      3. 15.2 Prokaryotic Transcription
      4. 15.3 Eukaryotic Transcription
      5. 15.4 RNA Processing in Eukaryotes
      6. 15.5 Ribosomes and Protein Synthesis
      7. Key Terms
      8. Chapter Summary
      9. Review Questions
      10. Critical Thinking Questions
      11. Test Prep for AP® Courses
      12. Science Practice Challenge Questions
    6. 16 Gene Regulation
      1. Introduction
      2. 16.1 Regulation of Gene Expression
      3. 16.2 Prokaryotic Gene Regulation
      4. 16.3 Eukaryotic Epigenetic Gene Regulation
      5. 16.4 Eukaryotic Transcriptional Gene Regulation
      6. 16.5 Eukaryotic Post-transcriptional Gene Regulation
      7. 16.6 Eukaryotic Translational and Post-translational Gene Regulation
      8. 16.7 Cancer and Gene Regulation
      9. Key Terms
      10. Chapter Summary
      11. Review Questions
      12. Critical Thinking Questions
      13. Test Prep for AP® Courses
      14. Science Practice Challenge Questions
    7. 17 Biotechnology and Genomics
      1. Introduction
      2. 17.1 Biotechnology
      3. 17.2 Mapping Genomes
      4. 17.3 Whole-Genome Sequencing
      5. 17.4 Applying Genomics
      6. 17.5 Genomics and Proteomics
      7. Key Terms
      8. Chapter Summary
      9. Review Questions
      10. Critical Thinking Questions
      11. Test Prep for AP® Courses
      12. Science Practice Challenge Questions
  5. Unit 4
    1. 18 Evolution and Origin of Species
      1. Introduction
      2. 18.1 Understanding Evolution
      3. 18.2 Formation of New Species
      4. 18.3 Reconnection and Rates of Speciation
      5. Key Terms
      6. Chapter Summary
      7. Review Questions
      8. Critical Thinking Questions
      9. Test Prep for AP® Courses
      10. Science Practice Challenge Questions
    2. 19 The Evolution of Populations
      1. Introduction
      2. 19.1 Population Evolution
      3. 19.2 Population Genetics
      4. 19.3 Adaptive Evolution
      5. Key Terms
      6. Chapter Summary
      7. Review Questions
      8. Critical Thinking Questions
      9. Test Prep for AP® Courses
      10. Science Practice Challenge Questions
    3. 20 Phylogenies and the History of Life
      1. Introduction
      2. 20.1 Organizing Life on Earth
      3. 20.2 Determining Evolutionary Relationships
      4. 20.3 Perspectives on the Phylogenetic Tree
      5. Key Terms
      6. Chapter Summary
      7. Review Questions
      8. Critical Thinking Questions
      9. Test Prep for AP® Courses
      10. Science Practice Challenge Questions
  6. Unit 5
    1. 21 Viruses
      1. Introduction
      2. 21.1 Viral Evolution, Morphology, and Classification
      3. 21.2 Virus Infection and Hosts
      4. 21.3 Prevention and Treatment of Viral Infections
      5. 21.4 Other Acellular Entities: Prions and Viroids
      6. Key Terms
      7. Chapter Summary
      8. Review Questions
      9. Critical Thinking Questions
      10. Test Prep for AP® Courses
      11. Science Practice Challenge Questions
    2. 22 Prokaryotes: Bacteria and Archaea
      1. Introduction
      2. 22.1 Prokaryotic Diversity
      3. 22.2 Structure of Prokaryotes
      4. 22.3 Prokaryotic Metabolism
      5. 22.4 Bacterial Diseases in Humans
      6. 22.5 Beneficial Prokaryotes
      7. Key Terms
      8. Chapter Summary
      9. Review Questions
      10. Critical Thinking Questions
      11. Test Prep for AP® Courses
      12. Science Practice Challenge Questions
  7. Unit 6
    1. 23 Plant Form and Physiology
      1. Introduction
      2. 23.1 The Plant Body
      3. 23.2 Stems
      4. 23.3 Roots
      5. 23.4 Leaves
      6. 23.5 Transport of Water and Solutes in Plants
      7. 23.6 Plant Sensory Systems and Responses
      8. Key Terms
      9. Chapter Summary
      10. Review Questions
      11. Critical Thinking Questions
      12. Test Prep for AP® Courses
      13. Science Practice Challenge Questions
  8. Unit 7
    1. 24 The Animal Body: Basic Form and Function
      1. Introduction
      2. 24.1 Animal Form and Function
      3. 24.2 Animal Primary Tissues
      4. 24.3 Homeostasis
      5. Key Terms
      6. Chapter Summary
      7. Review Questions
      8. Critical Thinking Questions
      9. Test Prep for AP® Courses
    2. 25 Animal Nutrition and the Digestive System
      1. Introduction
      2. 25.1 Digestive Systems
      3. 25.2 Nutrition and Energy Production
      4. 25.3 Digestive System Processes
      5. 25.4 Digestive System Regulation
      6. Key Terms
      7. Chapter Summary
      8. Review Questions
      9. Critical Thinking Questions
      10. Test Prep for AP® Courses
      11. Science Practice Challenge Questions
    3. 26 The Nervous System
      1. Introduction
      2. 26.1 Neurons and Glial Cells
      3. 26.2 How Neurons Communicate
      4. 26.3 The Central Nervous System
      5. 26.4 The Peripheral Nervous System
      6. 26.5 Nervous System Disorders
      7. Key Terms
      8. Chapter Summary
      9. Review Questions
      10. Critical Thinking Questions
      11. Test Prep for AP® Courses
      12. Science Practice Challenge Questions
    4. 27 Sensory Systems
      1. Introduction
      2. 27.1 Sensory Processes
      3. 27.2 Somatosensation
      4. 27.3 Taste and Smell
      5. 27.4 Hearing and Vestibular Sensation
      6. 27.5 Vision
      7. Key Terms
      8. Chapter Summary
      9. Review Questions
      10. Critical Thinking Questions
      11. Science Practice Challenge Questions
    5. 28 The Endocrine System
      1. Introduction
      2. 28.1 Types of Hormones
      3. 28.2 How Hormones Work
      4. 28.3 Regulation of Body Processes
      5. 28.4 Regulation of Hormone Production
      6. 28.5 Endocrine Glands
      7. Key Terms
      8. Chapter Summary
      9. Review Questions
      10. Critical Thinking Questions
      11. Test Prep for AP® Courses
      12. Science Practice Challenge Questions
    6. 29 The Musculoskeletal System
      1. Introduction
      2. 29.1 Types of Skeletal Systems
      3. 29.2 Bone
      4. 29.3 Joints and Skeletal Movement
      5. 29.4 Muscle Contraction and Locomotion
      6. Key Terms
      7. Chapter Summary
      8. Review Questions
      9. Critical Thinking Questions
      10. Science Practice Challenge Questions
    7. 30 The Respiratory System
      1. Introduction
      2. 30.1 Systems of Gas Exchange
      3. 30.2 Gas Exchange across Respiratory Surfaces
      4. 30.3 Breathing
      5. 30.4 Transport of Gases in Human Bodily Fluids
      6. Key Terms
      7. Chapter Summary
      8. Review Questions
      9. Critical Thinking Questions
      10. Test Prep for AP® Courses
      11. Science Practice Challenge Questions
    8. 31 The Circulatory System
      1. Introduction
      2. 31.1 Overview of the Circulatory System
      3. 31.2 Components of the Blood
      4. 31.3 Mammalian Heart and Blood Vessels
      5. 31.4 Blood Flow and Blood Pressure Regulation
      6. Key Terms
      7. Chapter Summary
      8. Review Questions
      9. Critical Thinking Questions
      10. Test Prep for AP® Courses
      11. Science Practice Challenge Questions
    9. 32 Osmotic Regulation and Excretion
      1. Introduction
      2. 32.1 Osmoregulation and Osmotic Balance
      3. 32.2 The Kidneys and Osmoregulatory Organs
      4. 32.3 Excretion Systems
      5. 32.4 Nitrogenous Wastes
      6. 32.5 Hormonal Control of Osmoregulatory Functions
      7. Key Terms
      8. Chapter Summary
      9. Review Questions
      10. Critical Thinking Questions
      11. Test Prep for AP® Courses
    10. 33 The Immune System
      1. Introduction
      2. 33.1 Innate Immune Response
      3. 33.2 Adaptive Immune Response
      4. 33.3 Antibodies
      5. 33.4 Disruptions in the Immune System
      6. Key Terms
      7. Chapter Summary
      8. Review Questions
      9. Critical Thinking Questions
      10. Test Prep for AP® Courses
      11. Science Practice Challenge Questions
    11. 34 Animal Reproduction and Development
      1. Introduction
      2. 34.1 Reproduction Methods
      3. 34.2 Fertilization
      4. 34.3 Human Reproductive Anatomy and Gametogenesis
      5. 34.4 Hormonal Control of Human Reproduction
      6. 34.5 Fertilization and Early Embryonic Development
      7. 34.6 Organogenesis and Vertebrate Formation
      8. 34.7 Human Pregnancy and Birth
      9. Key Terms
      10. Chapter Summary
      11. Review Questions
      12. Critical Thinking Questions
      13. Test Prep for AP® Courses
      14. Science Practice Challenge Questions
  9. Unit 8
    1. 35 Ecology and the Biosphere
      1. Introduction
      2. 35.1 The Scope of Ecology
      3. 35.2 Biogeography
      4. 35.3 Terrestrial Biomes
      5. 35.4 Aquatic Biomes
      6. 35.5 Climate and the Effects of Global Climate Change
      7. Key Terms
      8. Chapter Summary
      9. Review Questions
      10. Critical Thinking Questions
      11. Test Prep for AP® Courses
      12. Science Practice Challenge Questions
    2. 36 Population and Community Ecology
      1. Introduction
      2. 36.1 Population Demography
      3. 36.2 Life Histories and Natural Selection
      4. 36.3 Environmental Limits to Population Growth
      5. 36.4 Population Dynamics and Regulation
      6. 36.5 Human Population Growth
      7. 36.6 Community Ecology
      8. 36.7 Behavioral Biology: Proximate and Ultimate Causes of Behavior
      9. Key Terms
      10. Chapter Summary
      11. Review Questions
      12. Critical Thinking Questions
      13. Test Prep for AP® Courses
      14. Science Practice Challenge Questions
    3. 37 Ecosystems
      1. Introduction
      2. 37.1 Ecology for Ecosystems
      3. 37.2 Energy Flow through Ecosystems
      4. 37.3 Biogeochemical Cycles
      5. Key Terms
      6. Chapter Summary
      7. Review Questions
      8. Critical Thinking Questions
      9. Test Prep for AP® Courses
      10. Science Practice Challenge Questions
    4. 38 Conservation Biology and Biodiversity
      1. Introduction
      2. 38.1 The Biodiversity Crisis
      3. 38.2 The Importance of Biodiversity to Human Life
      4. 38.3 Threats to Biodiversity
      5. 38.4 Preserving Biodiversity
      6. Key Terms
      7. Chapter Summary
      8. Review Questions
      9. Critical Thinking Questions
      10. Test Prep for AP® Courses
  10. A | The Periodic Table of Elements
  11. B | Geological Time
  12. C | Measurements and the Metric System
  13. Index

In this section, you will explore the following questions:

  • What are examples of internal and external mechanisms that control the cell cycle?
  • What molecules are involved in controlling the cell cycle through positive and negative regulation?

Connection for AP® Courses

Each step of the cell cycle is closely monitored by external signals and internal controls called checkpoints. There are three major checkpoints in the cell cycle: one near the end of G1, a second at the G2/M transition, and the third during metaphase. Growth factor proteins arriving at the dividing cell’s plasma membrane can trigger the cell to begin dividing. Cyclins and cyclin-dependent kinases (Cdks) are internal molecular signals that regulate cell transitions through the various checkpoints. Passage through the G1 checkpoint makes sure that the cell is ready for DNA replication in the S stage of interphase; passage through the G2 checkpoint triggers the separation of chromatids during mitosis. Positive regulator molecules like the cyclins and Cdks allow the cell cycle to advance to the next stage; negative regulator molecules, such as tumor suppressor proteins, monitor cellular conditions and can halt the cycle until specific requirements are met. Errors in the regulation of the cell cycle can cause cancer, which is characterized by uncontrolled cell division.

Information presented and the examples highlighted in the section support concepts and Learning Objectives outlined in Big Idea 3 of the AP® Biology Curriculum Framework, as shown in the tables. The Learning Objectives listed in the Curriculum Framework provide a transparent foundation for the AP® Biology course, an inquiry-based laboratory experience, instructional activities, and AP® exam questions. A Learning Objective merges required content with one or more of the seven Science Practices.

Big Idea 3 Living systems store, retrieve, transmit and respond to information essential to life processes.
Enduring Understanding 3.A Heritable information provides for continuity of life.
Essential Knowledge 3.A.2 In eukaryotes, heritable information is passed to the next generation via processes that include the cell cycle and mitosis or meiosis plus fertilization.
Science Practice 6.4 The student can make claims and predictions about natural phenomena based on scientific theories and models.
Learning Objective 3.7 The student can make predictions about natural phenomena occurring during the cell cycle.
Essential Knowledge 3.A.2 In eukaryotes, heritable information is passed to the next generation via processes that include the cell cycle and mitosis or meiosis plus fertilization.
Science Practice 1.2 The student can describe representations and models of natural or man-made phenomena and systems in the domain.
Learning Objective 3.8 The student can describe the events that occur in the cell cycle.

Teacher Support

Introduce the topic of control of the cell cycle using visuals such as this video.

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 G0 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 G1 phase lasts approximately nine hours, the S phase lasts 10 hours, the G2 phase lasts about four and one-half hours, and the M phase lasts approximately one-half hour. In early embryos of fruit flies, the cell cycle is completed in about eight minutes. The timing of events in the cell cycle is controlled by mechanisms that are both internal and external to the cell.

Regulation of the Cell Cycle by External Events

Both the initiation and inhibition of cell division are triggered by events external to the cell when it is about to begin the replication process. An event may be as simple as the death of a nearby cell or as 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.

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.

Regulation at Internal Checkpoints

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 G1, at the G2/M transition, and during metaphase (Figure 10.11).

This illustration shows the three major checkpoints of the cell cycle: G_{1}, G_{2}, and M.
Figure 10.11 The cell cycle is controlled at three checkpoints. The integrity of the DNA is assessed at the G1 checkpoint. Proper chromosome duplication is assessed at the G2 checkpoint. Attachment of each kinetochore to a spindle fiber is assessed at the M checkpoint.

The G1 Checkpoint

The G1 checkpoint determines whether all conditions are favorable for cell division to proceed. The G1 checkpoint, also called the restriction point (in yeast), is a point at which the cell commits to the cell division process. External influences, such as growth factors, play a large role in carrying the cell past the G1 checkpoint. In addition to adequate reserves and cell size, there is a check for genomic DNA damage at the G1 checkpoint. A cell that does not meet all the requirements will not be allowed to progress into the S phase. The cell can halt the cycle and attempt to remedy the problematic condition, or the cell can advance into G0 and await further signals when conditions improve.

The G2 Checkpoint

The G2 checkpoint bars entry into the mitotic phase if certain conditions are not met. As at the G1 checkpoint, cell size and protein reserves are assessed. However, the most important role of the G2 checkpoint is to ensure that all of the chromosomes have been replicated and that the replicated DNA is not damaged. If the checkpoint mechanisms detect problems with the DNA, the cell cycle is halted, and the cell attempts to either complete DNA replication or repair the damaged DNA.

The M Checkpoint

The M checkpoint occurs near the end of the metaphase stage of karyokinesis. The M checkpoint 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.

Link to Learning

Watch what occurs at the G1, G2, and M checkpoints by visiting this website to see an animation of the cell cycle.

Down Syndrome is a genetic, developmental condition caused by nondisjunction of chromosome 21 during meiosis. Explain how a problem with the spindle checkpoint can cause this to occur in the cell.
  1. Failure in spindle checkpoint results in the formation of one gamete cell with two extra chromosomes and another gamete cell lacking chromosomes.
  2. Failure in spindle checkpoint yields the same number of chromosomes in each gamete cell.
  3. Failure in spindle checkpoint will form two gamete cells without any chromosomes.
  4. Failure in spindle checkpoint results in the formation of one gamete cell with an extra chromosome and another gamete cell lacking a chromosome.

Regulator Molecules of the Cell Cycle

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.

Positive Regulation of the Cell Cycle

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 10.12). 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.

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.
Figure 10.12 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)

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 10.13). 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.

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.
Figure 10.13 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.

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.

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.

Negative Regulation of the Cell Cycle

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.

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.

Rb, p53, and p21 act primarily at the G1 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 G1. 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 death, 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.

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 10.14). 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 G1/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.”

Visual Connection

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.
Figure 10.14 Rb halts the cell cycle and releases its hold in response to cell growth.
Rb and other proteins that negatively regulate the cell cycle are sometimes called tumor supressors. Why do you think the name tumor suppressor might be appropriate for these proteins?
  1. They inhibit cell division.
  2. They enhance the rate of cell division.
  3. They start the cell cycle, thereby suppressing tumor formation.
  4. These proteins, when phosphorylated, allow the cell cycle to proceed.

Science Practice Connection for AP® Courses

Think About It

  • Rb is a negative regulator that blocks the cell cycle at the G1 checkpoint until the cell achieves a requisite size. What is the most likely mechanism that Rb employs to halt the cell cycle?
  • A cell has a mutation that results in the production of an abnormal cyclin-dependent kinase at the G2/M checkpoint. What is a likely consequence of the mutation on the cell cycle?

Teacher Support

The Think About It questions are applications of Learning Objective 3.7 and Science Practice 6.4 and Learning Objective 3.8 and Science Practice 1.2 because the students are making predictions based on their understanding of the events occurring during the cell cycle.

Answers

  • Rb is active when it is dephosphorylated. In this state, Rb binds to E2F, which is a transcription factor required for the transcription and eventual translation of molecules required for the G1/S transition. E2F cannot transcribe certain genes when it is bound to Rb. As the cell increases in size, Rb becomes phosphorylated, inactivated, and releases E2F. E2F can then promote the transcription of the genes it controls, and the transition proteins will be produced.
  • Cyclins and cyclin-dependent kinases (Cdks), are responsible for the progress of the cell through the various checkpoints including the G2/M checkpoint. Without a specific concentration of fully activated cyclin/Cdk complexes, or if an abnormal cdk is produced, the cell cycle cannot proceed through the checkpoint and will arrest at the G2/M checkpoint.
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