Cell Cycle and Regulation

Cell Cycle Phases - The Cellular Racetrack

The cell cycle orchestrates cell duplication. It consists of Interphase (G1, S, G2) and M phase.

• Interphase: Preparatory phase for cell division.
  • G1 (Gap 1): Cell growth, protein & organelle synthesis. Longest & most variable phase. Restriction point commitment.
  • S (Synthesis): DNA replication. DNA content doubles ($\mathbf{2c} \rightarrow \mathbf{4c}$); chromosome number ($\mathbf{2n}$) unchanged. Histone synthesis.
  • G2 (Gap 2): Further growth, synthesis of microtubules (tubulin), preparation for mitosis.
• M Phase (Mitosis): Nuclear division (karyokinesis) and cytoplasmic division (cytokinesis).
  • Phases: Prophase, Metaphase, Anaphase, Telophase (PMAT 📌).
  • Cytokinesis: Division of cytoplasm, forming two daughter cells.
• G0 Phase (Quiescent): Resting state; cells have exited the cycle. Can be temporary or permanent (terminally differentiated, e.g., neurons, skeletal muscle).

⭐ Cells in G0 phase are metabolically active but non-proliferative; they can re-enter the cell cycle if stimulated by appropriate growth factors (e.g., lymphocytes).

Cyclins & CDKs - The Cycle's Conductors

• Cyclins: Regulatory proteins; their levels oscillate, driving cell cycle progression. No intrinsic enzymatic activity.
• CDKs (Cyclin-Dependent Kinases): Catalytic serine/threonine kinases; levels generally stable. Activated by binding specific cyclins, then phosphorylate target proteins.
• Key Complexes & Roles:
  • Cyclin D + CDK4/6: Mid-G1 phase progression (mediates passage through Restriction point).
  • Cyclin E + CDK2: Late G1 to S transition; initiates DNA replication.
  • Cyclin A + CDK2: S phase progression and completion.
  • Cyclin B + CDK1 (MPF): G2 to M transition; drives mitosis (nuclear envelope breakdown, chromosome condensation). 📌 Mnemonic: "Drive Every Auto Bus" (Cyclins D, E, A, B for G1, G1/S, S, M phases respectively)
• CDK Inhibitors (CKIs): Fine-tune CDK activity. Two families:
  • INK4 family (e.g., p16): Inhibit CDK4/6.
  • CIP/KIP family (e.g., p21, p27): Inhibit broad range of CDKs.

⭐ MPF (Maturation Promoting Factor), composed of Cyclin B and CDK1, is crucial for initiating mitosis. Its activity peaks during metaphase and drops sharply at anaphase due to Cyclin B degradation via APC/C (Anaphase Promoting Complex/Cyclosome).

Checkpoints & Gatekeepers - Quality Control Central

Cell cycle checkpoints ensure genomic integrity, preventing errors that can lead to uncontrolled proliferation (cancer). Key proteins like p53 and Rb act as gatekeepers.

• G1/S Checkpoint (Restriction Point): "Point of no return."
  • Monitors: DNA damage, cell size, nutrients, growth factors.
  • Key players: p53, Rb.
• G2/M Checkpoint:
  • Monitors: DNA replication completion, DNA damage.
  • Ensures readiness for mitosis. MPF (Cdk1-Cyclin B) is crucial.
• Spindle Assembly Checkpoint (SAC): (Metaphase-Anaphase)
  • Monitors: Kinetochore-microtubule attachment.
  • Prevents aneuploidy.

⭐ p53, the "Guardian of the Genome," is mutated in over 50% of human cancers. Its activation triggers cell cycle arrest, senescence, or apoptosis.

Dysregulation & Disease - When Cycles Go Rogue

• Cancer: Key outcome of dysregulation.
  • Uncontrolled proliferation, genomic instability, invasiveness.
• Key Mechanisms:
  • Proto-oncogenes → Oncogenes: (e.g., Ras, MYC, Cyclin D) → Uncontrolled "Go" signals.
  • Tumor suppressors inactivated: (e.g., p53, Rb) → Loss of "Stop" signals.
    • p53 ("Guardian of Genome"): Mutations in >50% human cancers.
  • Checkpoint failure: DNA damage unrepaired, mutations accumulate.
• Therapeutic Targets:
  • CDK inhibitors (e.g., Palbociclib for HR+ breast cancer).
  • Targeted therapies for specific oncoproteins (e.g., Imatinib).

⭐ Li-Fraumeni syndrome: Inherited TP53 mutation; high risk of multiple cancers (sarcomas, breast, brain, leukemia).

High‑Yield Points - ⚡ Biggest Takeaways

• Cyclin-CDK complexes drive cell cycle; specific pairs for phase transitions.
• G1 checkpoint (Restriction point), regulated by Rb & p53, is key for commitment.
• S phase: DNA replication. G2 checkpoint: checks DNA integrity pre-mitosis.
• M phase checkpoint (Spindle assembly): checks chromosome segregation.
• p53 (tumor suppressor) induces cell cycle arrest or apoptosis on DNA damage.
• Rb protein inhibits E2F, blocking S phase entry; inactivated by G1 CDKs.
• Cancer often involves p53/Rb mutations or cell cycle protein dysregulation.