20.4 Cell Cycle Regulation and Apoptosis
3 min read•august 9, 2024
Cell cycle regulation ensures orderly cell division. Checkpoints monitor DNA integrity and chromosome alignment, halting progression if issues arise. and CDKs drive the cycle forward, while tumor suppressors like p53 and Rb prevent uncontrolled growth.
, or programmed cell death, maintains tissue homeostasis. It's triggered by external signals or internal stressors, involving caspase activation and mitochondrial changes. regulate this process, balancing cell survival and death.
Cell Cycle Regulation
Phases and Regulatory Proteins
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- Cell cycle consists of four distinct phases G1, S, G2, and M
- G1 (Gap 1) involves cell growth and preparation for DNA synthesis
- S (Synthesis) phase encompasses DNA replication
- G2 (Gap 2) prepares the cell for mitosis
- M (Mitosis) phase includes nuclear division and cytokinesis
- Cyclins function as regulatory proteins that control cell cycle progression
- Cyclin levels fluctuate throughout the cell cycle
- Different cyclin types (A, B, D, E) associate with specific phases
- act as catalytic subunits activated by cyclins
- CDK activity requires binding to specific cyclins
- CDK-cyclin complexes phosphorylate target proteins to drive cell cycle events
Checkpoint Mechanisms
- Checkpoint proteins monitor cell cycle progression and halt advancement if conditions are unfavorable
- DNA damage, incomplete replication, or improper chromosome alignment trigger checkpoints
- Checkpoints ensure genetic stability and prevent propagation of errors
- p53 serves as a tumor suppressor protein and transcription factor
- Activates in response to cellular stress or DNA damage
- Induces cell cycle arrest, DNA repair, or apoptosis
- Mutations in p53 gene contribute to cancer development
- regulates G1 to transition
- Inhibits E2F transcription factors when unphosphorylated
- CDK-mediated phosphorylation of Rb releases E2F, promoting S phase entry
- Rb dysfunction leads to uncontrolled cell proliferation
Apoptosis Pathways
Programmed Cell Death Mechanisms
- Apoptosis describes the process of programmed cell death
- Characterized by , chromatin condensation, and DNA fragmentation
- Vital for embryonic development, tissue homeostasis, and immune system function
- function as proteolytic enzymes central to apoptosis execution
- Exist as inactive zymogens and activate through proteolytic cleavage
- Initiator caspases (2, 8, 9, 10) activate effector caspases (3, 6, 7)
- Effector caspases cleave cellular proteins, leading to cell dismantling
- Bcl-2 family proteins regulate mitochondrial outer membrane permeabilization
- Pro-apoptotic members (Bax, Bak) promote release
- Anti-apoptotic members (Bcl-2, Bcl-xL) inhibit cytochrome c release
- BH3-only proteins (Bid, Bim) act as sensors of cellular stress
Apoptotic Signaling Pathways
- Death receptors initiate the extrinsic apoptosis pathway
- Belong to the tumor necrosis factor (TNF) receptor superfamily
- Fas and TNFR1 serve as well-characterized death receptors
- Ligand binding triggers receptor clustering and formation of
- Mitochondrial pathway represents the intrinsic apoptosis route
- Activated by internal cellular stressors (DNA damage, oxidative stress)
- Involves release of cytochrome c from mitochondria
- Cytochrome c forms apoptosome complex with and procaspase-9
- Apoptosome activates caspase-9, initiating the caspase cascade
Cell Cycle Checkpoints and DNA Damage Response
DNA Damage Detection and Repair
- DNA damage response (DDR) encompasses cellular mechanisms to detect and repair genetic lesions
- Sensor proteins (MRN complex, RPA) recognize DNA damage
- Transducer kinases (ATM, ATR) amplify and relay damage signals
- Effector proteins (p53, BRCA1) mediate cell cycle arrest and DNA repair
- G1/S checkpoint prevents cells with damaged DNA from entering S phase
- p53 activation leads to p21 induction, inhibiting CDK2-cyclin E
- Rb remains hypophosphorylated, blocking E2F-mediated transcription
- Allows time for DNA repair before replication initiation
Mitotic Entry and Spindle Assembly Regulation
- G2/M checkpoint ensures completion of DNA replication and repair before mitosis
- ATM/ATR activation leads to inhibition of CDC25 phosphatases
- Maintained inhibitory phosphorylation on CDK1 prevents mitotic entry
- WEE1 kinase activity opposes CDC25, maintaining G2 arrest
- Spindle assembly checkpoint (SAC) delays anaphase onset until proper chromosome attachment
- Monitors kinetochore-microtubule attachments and tension
- Unattached kinetochores generate "wait anaphase" signal
- Mad2, BubR1, and other SAC proteins inhibit APC/C-Cdc20 complex
- Proper attachments silence SAC, allowing chromosome segregation
Key Terms to Review (26)
Apaf-1: Apoptosis protease activating factor 1 (apaf-1) is a crucial protein involved in the process of apoptosis, which is programmed cell death. It plays a key role in the intrinsic pathway of apoptosis by forming a complex that activates caspases, the enzymes responsible for executing the death program in cells. The activity of apaf-1 is tightly regulated and is essential for maintaining cellular homeostasis and development.
Apoptosis: Apoptosis is a form of programmed cell death that plays a crucial role in maintaining the balance of cell populations in tissues and preventing the development of diseases such as cancer. It is a highly regulated process that enables cells to self-destruct in response to various internal and external signals, ensuring proper cellular turnover and homeostasis.
Bcl-2 family proteins: Bcl-2 family proteins are a group of regulators that play a critical role in the process of apoptosis, or programmed cell death. These proteins can be divided into pro-apoptotic and anti-apoptotic members, influencing cell survival and death decisions. Their balance determines cellular outcomes in response to stress and is essential for maintaining tissue homeostasis and preventing diseases such as cancer.
Blebbing: Blebbing refers to the formation of bulges or protrusions, called 'blebs,' on the surface of a cell during processes like apoptosis or cell death. This phenomenon is significant in the context of programmed cell death, as it represents a morphological change that occurs when cells are undergoing apoptosis, signaling the disassembly of cellular components and ultimately leading to cell clearance.
Bradford Assay: The Bradford assay is a colorimetric protein assay that uses Coomassie Brilliant Blue dye to determine protein concentration in a sample. This method is quick, easy, and sensitive, making it a popular choice for measuring protein levels in various biological samples, especially in the context of analyzing cell cycle regulation and apoptosis.
Caspases: Caspases are a family of cysteine proteases that play essential roles in programmed cell death, or apoptosis. These enzymes act as key regulators in the apoptosis pathway by cleaving specific substrates, which leads to the morphological and biochemical changes associated with cell death. They can also influence inflammation and cell differentiation, showing their importance beyond just apoptosis.
Cell shrinkage: Cell shrinkage refers to the reduction in cell volume, which can occur as a result of various physiological and pathological processes. This phenomenon is often associated with apoptosis, a form of programmed cell death, where cells undergo morphological changes that include shrinking and condensing of cellular components. Cell shrinkage is an important indicator of cellular health and is closely linked to the regulation of the cell cycle.
Cellular senescence: Cellular senescence is a state in which cells cease to divide and grow, often as a response to stress or damage, while remaining metabolically active. This process serves as a protective mechanism against cancer, limiting the proliferation of damaged cells, but it can also contribute to aging and age-related diseases due to the accumulation of senescent cells in tissues over time.
Checkpoint control: Checkpoint control refers to the regulatory mechanisms that ensure the proper progression of the cell cycle by monitoring key events and conditions at specific checkpoints. These checkpoints act as quality control systems that assess whether the cell is ready to proceed to the next phase, such as DNA replication, mitosis, or cytokinesis. They play a crucial role in maintaining genomic integrity and preventing the propagation of damaged or incomplete DNA, ultimately influencing cell survival and apoptosis.
Cyclin-dependent kinases (cdks): Cyclin-dependent kinases (cdks) are a family of protein kinases that play a crucial role in regulating the cell cycle by phosphorylating target proteins, which is essential for the progression through different phases of the cycle. They are activated when bound to specific regulatory proteins called cyclins, forming a complex that triggers various cellular processes including DNA replication and cell division. This regulation is vital for maintaining proper cell function and preventing uncontrolled cell growth, which can lead to cancer.
Cyclins: Cyclins are a family of proteins that play a crucial role in regulating the cell cycle by activating cyclin-dependent kinases (CDKs). These proteins are characterized by their periodic synthesis and degradation, which ensures that specific phases of the cell cycle proceed in a controlled manner. Cyclins bind to CDKs, forming active complexes that drive the cell through various checkpoints, coordinating cell division and preventing errors that could lead to abnormal growth or apoptosis.
Cytochrome c: Cytochrome c is a small heme protein found in the mitochondria that plays a critical role in the electron transport chain, where it functions as an electron carrier. It transfers electrons between complex III and complex IV, contributing to the proton gradient essential for ATP synthesis through oxidative phosphorylation. This protein also has important implications in apoptosis, serving as a signaling molecule that can trigger cell death when released into the cytosol.
Death-inducing signaling complex (DISC): The death-inducing signaling complex (DISC) is a multiprotein complex formed in response to pro-apoptotic signals, such as those from death receptors on the cell surface. It plays a critical role in the initiation of apoptosis by facilitating the activation of caspases, which are essential enzymes for programmed cell death. The formation of DISC is a key step in the apoptotic pathway and links external signals to the intrinsic cellular mechanisms that ultimately lead to cell death.
Dna repair mechanisms: DNA repair mechanisms are processes by which a cell identifies and corrects damage to its DNA molecules, ensuring the integrity of the genetic information. These mechanisms are crucial for maintaining genomic stability, preventing mutations, and supporting cellular functions such as cell cycle regulation and apoptosis. Effective DNA repair plays a vital role in protecting cells from the harmful effects of environmental factors and cellular processes that can lead to DNA damage.
Extrinsic pathway: The extrinsic pathway is a crucial mechanism in the process of apoptosis, where cell death is initiated through external signals binding to death receptors on the cell membrane. This pathway typically involves the activation of specific receptors, such as Fas and TNF receptors, leading to a cascade of intracellular events that ultimately activate caspases, the enzymes responsible for executing the cell death program. It highlights the importance of external factors in regulating cellular life and death, connecting the roles of signaling molecules and receptors in cell cycle regulation.
G1 Phase: The G1 phase is the first stage of interphase in the cell cycle, occurring after cell division and before DNA synthesis begins. It is a critical period where the cell grows, synthesizes proteins, and prepares for DNA replication. During G1, the cell also assesses its environment and decides whether to proceed to the next phase based on internal and external signals.
G2 Phase: The G2 phase is the third subphase of interphase in the cell cycle, occurring after DNA synthesis in the S phase and before mitosis. During this phase, the cell undergoes further growth and prepares itself for division, ensuring all cellular components are ready and intact. The G2 phase is crucial for checking DNA replication errors, organizing the cytoskeleton, and synthesizing proteins needed for mitosis.
HeLa Cells: HeLa cells are a line of human cervical cancer cells that were taken from Henrietta Lacks in 1951 and have been used extensively in scientific research. They are notable for their ability to divide indefinitely in laboratory conditions, making them a valuable tool for studying cell biology, cancer, and various medical research applications. HeLa cells have played a significant role in advancements in understanding the cell cycle and apoptosis, providing insights into how cells regulate growth and respond to death signals.
Intrinsic pathway: The intrinsic pathway refers to a specific signaling cascade that triggers apoptosis, or programmed cell death, within a cell. This pathway is activated in response to internal signals such as DNA damage or cellular stress, leading to the activation of caspases, which are crucial enzymes that execute the cell death program. The intrinsic pathway is a critical component of cell cycle regulation and plays a significant role in maintaining cellular homeostasis by eliminating damaged or unwanted cells.
M phase: The m phase, or mitotic phase, is a stage in the cell cycle where cell division occurs, resulting in the formation of two daughter cells. This phase includes both mitosis, the process of nuclear division, and cytokinesis, the division of the cytoplasm. Proper regulation of the m phase is crucial for maintaining genetic stability and overall cellular health.
Oncogenes: Oncogenes are mutated versions of normal genes, known as proto-oncogenes, that promote cell division and growth. When these genes become activated due to mutations, they can lead to uncontrolled cell proliferation, contributing to the development of cancer. Oncogenes play a crucial role in the regulation of the cell cycle and apoptosis, influencing how cells respond to various growth signals.
P53 pathway: The p53 pathway is a crucial signaling network that regulates the cell cycle, DNA repair, and apoptosis in response to cellular stress or DNA damage. It is often referred to as the 'guardian of the genome' because of its role in maintaining genomic stability by preventing the propagation of damaged DNA. When activated, p53 can induce cell cycle arrest, DNA repair mechanisms, or trigger apoptosis if the damage is irreparable.
Ras signaling pathway: The ras signaling pathway is a crucial molecular cascade that relays signals from cell surface receptors to the nucleus, playing a vital role in regulating cell growth, differentiation, and survival. This pathway is often activated by growth factors binding to receptor tyrosine kinases, which then activate ras proteins, leading to a series of downstream signaling events that ultimately influence the cell cycle and apoptosis.
Retinoblastoma protein (Rb): The retinoblastoma protein (Rb) is a crucial tumor suppressor that regulates the cell cycle and prevents uncontrolled cell growth. It functions primarily by inhibiting the transition from the G1 phase to the S phase of the cell cycle, thus acting as a gatekeeper for cellular proliferation. Rb's activity is influenced by phosphorylation, which can lead to its inactivation, allowing cells to proceed through the cell cycle and potentially leading to tumorigenesis when regulation fails.
S Phase: The S phase, or synthesis phase, is a critical part of the cell cycle where DNA replication occurs, leading to the duplication of chromosomes. This phase ensures that each daughter cell receives an identical set of genetic information during cell division, which is essential for maintaining genetic stability and proper cellular function.
Tumor suppressor genes: Tumor suppressor genes are segments of DNA that help regulate cell growth and division, playing a crucial role in preventing the formation of tumors. When these genes are functioning properly, they produce proteins that inhibit cell division or promote apoptosis, effectively acting as a safeguard against cancer. Mutations or deletions in tumor suppressor genes can lead to uncontrolled cell proliferation, contributing to cancer development.