Cell cycle regulation ensures orderly cell division. Checkpoints monitor DNA integrity and chromosome alignment, halting progression if issues arise. Cyclins and CDKs drive the cycle forward, while tumor suppressors like p53 and Rb prevent uncontrolled growth.
Apoptosis, or programmed cell death, maintains tissue homeostasis. It's triggered by external signals or internal stressors, involving caspase activation and mitochondrial changes. Bcl-2 family proteins 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
- Cyclin-dependent kinases (CDKs) 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
- Retinoblastoma protein (Rb) regulates G1 to S phase 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 cell shrinkage, chromatin condensation, and DNA fragmentation
- Vital for embryonic development, tissue homeostasis, and immune system function
- Caspases 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 cytochrome c 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 death-inducing signaling complex (DISC)
- 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 Apaf-1 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