Cell Growth and Division PDF

**Cell Growth and Division** Introduction Cellular reproduction is at the heart of the modern cell theory, which holds that the cell is the structural and functional unit of all living things and that all cells come from pre-existing cells. A single cell cycle begins at the end of the previous cel...

**Cell Growth and Division** Introduction Cellular reproduction is at the heart of the modern cell theory, which holds that the cell is the structural and functional unit of all living things and that all cells come from pre-existing cells. A single cell cycle begins at the end of the previous cell\'s reproductive process (ie, cell division) and ends when that cell completes division and becomes two new cells. Cell division serves as a method of reproduction for single-celled organisms. For multicellular organisms, cell division serves several purposes: to facilitate the growth and development of the organism and to replace old or damaged cells. This lesson provides a general understanding of what happens during the lifespan of a single cell (the cell cycle), focusing closely on the steps and regulation of cell division. 5.4.01 The Cell Cycle The continuity of life depends on the successful reproduction of cells and organisms. During its life span, a cell passes through a set of highly regulated phases, known as the **cell cycle**. The most important function of the cell cycle is to facilitate the duplication and segregation of the cell\'s genetic information to form two identical daughter cells. The two major phases of the eukaryotic [cell cycle](javascript:void(0)) are defined as **interphase** and **mitotic (M) phase** (Figure 5.52). The cell spends approximately 90% of its life cycle in interphase, which can be further divided into three distinct parts: **G1 phase** (first gap phase), **S phase** (synthesis), and **G2 phase** (second gap phase). Each phase is characterized by distinctive cellular activities. Cell division in prokaryotic organisms occurs via a different mechanism known as binary fission, which is covered in Concept 6.2.01. Chapter 5: Eukaryotic Cells 194 **Figure 5.52** Major phases of the cell cycle. During G1 phase, the cell enters a growth period in which it produces proteins, stores energy, and assembles new organelles and other molecular machinery. If conditions are favorable, the cell transitions to S phase, during which its DNA is replicated (Figure 5.53). From the end of S phase until chromosomes are separated during mitosis, a duplicate copy of each chromosome is present. A diagram of a cell growth cycle Description automatically generated Chapter 5: Eukaryotic Cells 195 **Figure 5.53** The genome is replicated during S phase. During G2 phase, the cell replenishes energy stores, synthesizes proteins, and assembles the molecular machinery required to prepare for cell division. Cellular organelles are prepared for partitioning into daughter cells, and any errors in DNA replication are repaired. Once the final preparations for cell division have been made, the transition to M phase can take place. Two concurrent events are initiated during M phase: mitosis and cytokinesis. **Mitosis** involves the segregation of duplicated chromosomes (nuclear division), while the cell itself is pinched in half during **cytokinesis** (cytoplasmic division) to form two identical daughter cells. In most cases, after completing G1 phase the cell enters a specialized resting state known as **G0 phase**, in which the cell cycle is arrested for a variable period of time depending on cell type and environmental conditions. Some cells may remain in G0 permanently. For example, during neuronal differentiation, most differentiated neurons enter G0 and permanently withdraw from the cell cycle. 5.4.02 The Mitotic Process During the latter part of interphase (S and G2 phases), the cell is committed to dividing and completes preparations for the final phase of the cell cycle, the **mitotic (M) phase**. At the beginning of mitosis, each duplicated chromosome consists of two identical **sister chromatids**. Each sister chromatid is made up of DNA and its associated proteins and contains a region of repetitive DNA sequences known as a **centromere**, which is where the two sister chromatids are joined, as shown in Figure 5.54. At the end of mitosis, sister chromatids separate from each other and are pulled to opposite ends of the cell. Once chromatids separate (ie, during anaphase of mitosis), they are no longer considered sister chromatids, but individual (unduplicated) chromosomes, and one chromosome is partitioned into each of the two daughter cells. Therefore, at the beginning of the next cell cycle, each daughter cell contains an identical set of unduplicated chromosomes derived from the parent cell.  Chapter 5: Eukaryotic Cells 196 **Figure 5.54** Unduplicated versus duplicated chromosomes. [Mitosis](javascript:void(0)) is conventionally broken down into four major stages: 1.**Prophase**: During this stage, chromosomes become heavily condensed due to chromatin compaction. At this time, individual chromosomes are observable under a light microscope and nucleoli are no longer visible. The nuclear envelope is broken down and the **mitotic spindle** is assembled. **Spindle fibers** are formed from microtubules originating from each centrosome (ie, microtubule organizing center). Spindle fibers on both sides of the duplicated chromosome (ie, one for each sister chromatid) bind to structures called **kinetochores**, which attach to the lateral region of each centromere near the end of prophase (Figure 5.55). During this time, nonkinetochore spindle fibers are also formed, and these fibers assist in elongation of the cell during the later stages of mitosis. As prophase continues, centrosomes migrate to opposite ends of the cell, partially propelled by the growing spindle fibers. A diagram of a blue cell Description automatically generated with medium confidence Chapter 5: Eukaryotic Cells 197 **Figure 5.55** Formation of the mitotic spindle begins during prophase. 2.**Metaphase**: By the end of prophase, the centrosomes are located at opposite ends of the cell with chromosomes attached to the spindle fibers. During metaphase, chromosomes are positioned at the "equator" of the cell, along the **metaphase plate**. (Note: Some sources recognize **prometaphase**, an additional stage of mitosis between prophase and metaphase, which combines the events of late prophase and early metaphase.) 3.**Anaphase**: Sister chromatids detach from one another at the centromeres as spindle fibers begin to shorten, pulling the sister chromatids in opposite directions. This results in the separation of sister chromatids, with one identical set of chromosomes segregated to each side of the cell. 4.**Telophase**: Two daughter nuclei form as nuclear envelopes reform around each set of chromosomes. Chromatin condensation relaxes, resulting in less dense chromosomes, and nucleoli reappear. Any remaining spindle fibers are dismantled. At the conclusion of telophase, the process of mitosis (ie, nuclear division) is complete, and the parent cell contains two genetically identical daughter nuclei (Figure 5.56).  Chapter 5: Eukaryotic Cells 198 **Figure 5.56** Stages of mitosis. **Cytokinesis**, or cytoplasmic division, is considered a separate but concurrent event overlapping with mitosis. In animal cells, cytokinesis begins during late anaphase when the cell begins to elongate and a shallow groove called the **cleavage furrow** forms at the cell surface near the original location of the metaphase plate. On the cytoplasmic side, the cleavage furrow is characterized by a contractile ring of microfilaments (actin) associated with myosin proteins. This association causes the ring to contract, progressively pinching the cell until the two new cells are completely separated from each other, each with its own nucleus, cytosol, and organelles (Figure 5.57). For organisms that contain a cell wall (eg, plants, algae), cytokinesis proceeds via an alternative mechanism. A diagram of a cell division Description automatically generated Chapter 5: Eukaryotic Cells 199 **Figure 5.57** Cytokinesis involves the formation of a cleavage furrow and contractile ring. **Concept Check 5.4** During which of the following stages of the cell cycle do cells contain duplicated chromosomes? [**Solution**](javascript:void(0)) 5.4.03 Cell Cycle Control The accurate timing and execution of cell cycle events is critical for organism growth, development, and reproduction. Dysregulation of the cell cycle control system can result in catastrophic effects, such as cell death or [cancer](javascript:void(0)) development. Therefore, an intrinsic timing mechanism monitoring both internal and external cellular conditions is essential for proper cell cycle control. This mechanism includes regulatory  A blue check mark in a square Description automatically generated  Chapter 5: Eukaryotic Cells 200 **checkpoints (restriction points)** that ensure proper execution of prior steps before entry into the next stage of the cycle. The three most important cell cycle checkpoints occur at the G1/S and G2/M transitions and during M (mitotic) phase, as depicted in Figure 5.58. Checkpoints can be used as mechanisms to promote or inhibit cell proliferation. In healthy cells, entry into the next stage of the cell cycle is prohibited if there are abnormalities in the preceding stages. Regulation of the G1/S checkpoint is particularly crucial because it commits the cell to completing a cell cycle. During the G2/M transition, entry into M phase is blocked if DNA replication is inaccurate or incomplete. If DNA is damaged by radiation or chemicals, progression to the next stage can be delayed until the damage is repaired. Likewise, during M phase, the separation of chromosomes at anaphase is delayed if chromosomes are not properly attached to the mitotic spindle. **Figure 5.58** Important cell cycle checkpoints. Cell cycle checkpoints are primarily regulated by proteins known as **cyclins** and **cyclin-dependent kinases (CDKs)**. The relative abundance and/or activity of these proteins fluctuate regularly during the cell cycle. As cyclins accumulate, they are activated by associating with a CDK partner. Activated cyclin-CDK complexes are able to phosphorylate a variety of proteins, advancing the cell through various cell cycle stages. Diagram of cell growth cycle Description automatically generated Chapter 5: Eukaryotic Cells 201 Cyclin proteins undergo cycles of synthesis and degradation during each cell cycle. Levels of individual CDKs remain constant throughout each cycle, but CDKs become active only when combined with the appropriate cyclin partner. Therefore, the activity of CDKs is dependent on the rise and fall of different cyclins at each cell cycle stage. Cyclin-CDK complexes are inactivated by the rapid proteolysis of the dominant cyclin at each stage, as shown in Figure 5.59. **Figure 5.59** Cyclin-CDK complexes regulate cell cycle checkpoints. Three major types of regulatory cyclins exist, and each is defined by the cell cycle stage in which it functions: **G1/S cyclins** bind to CDKs at the end of G1 and commit the cell to DNA replication. **S cyclins** peak during S phase and are required for DNA replication. **M cyclins** peak at the G2/M transition and promote the events of mitosis. In multicellular organisms, cell division and cell death must be counterbalanced to keep tissues and organs at an appropriate size. Therefore, regulation of cell death is equally important. **Apoptosis** (ie, **programmed cell death**) is a series of events that occurs as a result of this regulation. Unlike cell death via necrosis, apoptotic cells shrink and condense without damaging neighboring cells. The apoptotic process is mediated by a cascade of proteolytic enzymes called **caspases**. These enzymes are synthesized as inactive precursors known as procaspases. When activated, caspases cleave and activate other key proteins, leading to DNA fragmentation and disassembly of the cell into subcellular fragments. As the cell is dismantled, **apoptotic blebs** (ie, irregular bulges in the plasma membrane) are formed. As apoptosis progresses, the apoptotic blebs become separated from the cell undergoing apoptosis, forming  Chapter 5: Eukaryotic Cells 202 **apoptotic bodies**. Apoptotic bodies are phagocytosed, either by a neighboring cell or by specialized circulating phagocytic cells of the immune system, such as macrophages (Figure 5.60). **Figure 5.60** The process of apoptosis. Both chemical and physical external controls also play a role in the regulation of cell division. For example, if essential nutrients are not present, the cell cycle can become arrested. In addition to favorable internal and external conditions, most mammalian cell types require specific growth factors to progress past the G1/S checkpoint. Most healthy cells exhibit **density-dependent inhibition**, in which the number of cells present influences the rate of division, and **anchorage dependence**, in which cells must be attached to a surface (eg, extracellular matrix, a culture flask) to divide. These normal limits may be bypassed when the cell cycle is dysregulated, such as in cancer cells, discussed in more detail in Concept 5.4.04. A diagram of cell division Description automatically generated Chapter 5: Eukaryotic Cells 203 5.4.04 Cancer When signals and cell cycle checkpoints are ignored, cells may continue to divide inappropriately, and cancerous cells may develop. **Cancer** can arise when cells begin to make their own growth factors or when cells have abnormalities in the signaling pathways responsible for conveying signals to the cell cycle control system. Alternatively, cells may have defects in the cell cycle control system itself. Most cancers arise from the accumulation of *multiple* genetic defects in one or more of these pathways that allow for uncontrolled cell division without compensation from the normal rate of apoptosis (programmed cell death) (Figure 5.61). **Figure 5.61** Multiple genetic defects can contribute to cell cycle dysregulation and cancer. A typical cell divides approximately 20--50 times before undergoing programmed cell death. Under typical conditions, the shortening of telomeres (chromosomal ends) during progressive rounds of replication usually leads to a finite cellular life span, as discussed in Concept 1.2.04. Once telomeres shorten past a critical point, the cell cycle control system promotes **senescence**, or growth arrest (see Figure 5.62).  Chapter 5: Eukaryotic Cells 204 **Figure 5.62** When telomeres shorten past a critical point, cells cease to divide. In contrast to healthy cells, cancerous cells continue to proliferate beyond their expected lifespan. When this proliferation occurs indefinitely, cells are considered \"immortal.\" Inappropriate expression of the enzyme **telomerase** is one reason cells are able to continue dividing beyond their expected lifespan. Telomerase replenishes chromosome ends by adding new telomeric DNA repeats at the ends of chromosomes. Therefore, in cells where telomerase is expressed, chromosome ends are constantly replenished with new telomeric repeats and cell division may occur indefinitely. Telomerase consists of the protein subunit telomerase reverse transcriptase (TERT) and a type of noncoding RNA called telomerase RNA (TR). Using TR as a template, TERT extends telomeres by repeatedly adding the sequence 5′-TTAGGG-3′ to chromosome ends. Once the telomere sequence reaches a sufficient length, DNA polymerase is able to synthesize a complementary DNA strand (Figure 5.63). Therefore, the extension of telomeres allows cells (eg, cancer cells) to avoid senescence. Senescence and aging are covered in more detail in Concept 10.5.02. A diagram of cell division Description automatically generated Chapter 5: Eukaryotic Cells 205 **Figure 5.63** Telomerase extends telomeres.  Chapter 5: Eukaryotic Cells 206 The regulation of cell growth and division is controlled by many genes, such as genes that encode growth factors and their receptors, intracellular signaling pathways, and molecules responsible for cell cycle regulation. [Mutations](javascript:void(0)) in any of these genes in somatic cells may lead to unregulated cell growth and ultimately cancer. These mutations may be inherited or can be acquired from environmental exposure to chemical or physical [mutagens](javascript:void(0)) such as tobacco products, radiation, and certain viruses. An **oncogene** is a mutated gene that has the potential to cause cancer. **Proto-oncogenes** are the wild-type version of these genes, and they code for proteins that promote regulated cell growth and appropriate division. An activating mutation in at least one allele of a proto-oncogene may convert the proto-oncogene into an oncogene and result in inappropriate activation of the gene or its protein product. Oncogenes promote uncontrolled cell growth and cancer, as shown in Figure 5.64. Proto-oncogenes may become oncogenes via various mechanisms, including point mutations, epigenetic changes, and chromosomal rearrangements (see Lesson 2.3 and Lesson 7.3). In addition to point mutations in the coding regions of a proto-oncogene, mutations in regulatory regions (eg, promoter, enhancer) can also change gene expression levels (see Concept 2.4.03). **Figure 5.64** Conversion of a proto-oncogene to an oncogene. Multiple classes of oncogenes exist, including genes that code for growth factors (eg, PDGF), growth factor receptors (eg, HER2), signal transduction proteins (eg, Ras), and transcription factors (eg, Myc). The **c-Myc** gene encodes a transcription factor activated in diverse signaling pathways under typical conditions. When c-Myc expression or activity is upregulated, genes involved in cell growth and metabolism are stimulated, leading to increased cell proliferation. Mutations in c-Myc are also associated with cancer progression from more benign to more invasive forms. Genes that typically function to repress cell division are called **tumor suppressor genes**. Mutations leading to decreased tumor suppressor gene activity may also contribute to cancer development because cells become able to bypass checkpoint activities (Figure 5.65). Unlike proto-oncogenes, tumor suppressor genes typically require mutations in *both* alleles to have an effect on cell cycle regulation. In many cases, individuals inherit a mutation in one allele, and the second allele undergoes mutation at some point during the individual\'s lifetime, leading to loss of cell cycle control. Tumor suppressor genes play various roles in cell cycle regulation. Some are involved in DNA repair and prevent the accumulation of mutations that promote cancer formation. Other tumor suppressor genes are involved in maintaining anchorage dependence and contact inhibition, which are often absent in cancerous cells (see Concept 5.4.03). Some of these genes are directly or indirectly involved in cell signaling pathways that control growth and proliferation. A diagram of a cell division Description automatically generated Chapter 5: Eukaryotic Cells 207 **Figure 5.65** Inactivating mutations in both alleles of a tumor suppressor gene lead to uncontrolled cell growth. The **p53** gene is a tumor suppressor gene that codes for a [transcription factor](javascript:void(0)) activated in response to various distress signals, including DNA damage, hypoxia (ie, low oxygen levels), and nutrient deprivation. In response to these signals, p53 promotes appropriate response pathways, including activation of DNA repair enzymes and cyclin-dependent kinase (CDK) inhibitors, which pause the cell cycle until the threat has been appropriately addressed. If cell damage is irreparable or a threat continues, p53 activates apoptotic pathways, resulting in damaged cells undergoing apoptosis so only undamaged cells finish the cell cycle. In the absence of p53 activity, these protective pathways are not activated, and cell cycle progression is uncontrolled