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Cell Cycle Regulation: Checkpoints, Regulators & Cancer Biology
1. Cell Cycle Checkpoints
- G1/S Phase Checkpoint: Ensures the cell is ready for DNA replication.
- G2/M Phase Checkpoint: Verifies DNA has been accurately duplicated without damage.
- Spindle Checkpoint (also known as M Checkpoint): Confirms chromosomes are attached correctly to the spindle microtubules for equal separation.
2. Positive Regulation of the Cell Cycle
Controlled by cyclins and cyclin-dependent kinases (Cdks) that drive cell progression:
- Specific cyclins rise and fall at each checkpoint.
- Cyclins activate Cdks only when tightly bound.
- To be fully functional, the Cdk/cyclin complex must be phosphorylated in specific locations.
3. Negative Regulation of the Cell Cycle
Negative regulators halt the cycle. The most studied molecule is p53.
- p53 detects damaged DNA during G1 phase.
- It halts the cycle and recruits repair enzymes.
- If damage is irreparable, p53 initiates apoptosis (cell suicide).
4. External Controls of Cell Division
- Growth Factors: Proteins that stimulate cell division.
- Density-Dependent Inhibition: Crowded cells stop dividing when they touch each other.
- Anchorage Dependence: Cells must be attached to a surface (like tissue matrix or dish) to divide.
Cancer cells ignore both density inhibition and anchorage dependence and continue dividing uncontrollably.
5. Cancer: When Regulation Fails
If regulators like p53 malfunction, cells with damaged DNA may continue to divide, leading to cancer.
Cancer cells:
- Do not stop at checkpoints.
- Ignore external inhibitory signals.
- Divide even in absence of anchorage.
| Category | Component/Phase | Function/Description |
|---|---|---|
| Checkpoint | G1/S Phase Checkpoint | Ensures the cell is ready to start DNA replication. |
| Checkpoint | G2/M Phase Checkpoint | Ensures DNA has been copied without major errors. |
| Checkpoint | Spindle Checkpoint (M Checkpoint) | Ensures all chromosomes are properly attached to spindle fibers for accurate separation. |
| Positive Regulation | Cyclins | Regulate different stages of the cell cycle by activating Cdks when bound together. |
| Positive Regulation | Cyclin-dependent kinases (Cdks) | Phosphorylate specific target proteins to advance the cell through cycle checkpoints. |
| Negative Regulation | p53 Protein | Stops the cycle if DNA is damaged. Repairs DNA or triggers apoptosis if damage is irreparable, thus preventing tumor formation. |
Presented by Prof. Siddharth Sanghvi Sir | BSI Sir | | SIDD Sir |
|| ALLEN’s The 3 Musketeers – Excellence in Biology ||
Team Members: Cyclin D, CDK4/6, Retinoblastoma protein (Rb), E2F transcription factors
Objective: To assess if the cell is ready to enter S phase (DNA synthesis)
Modus Operandi: Growth factors stimulate Cyclin D production → Activates CDK4/6 → Phosphorylates Rb → Releases E2F → Triggers genes for DNA replication. If DNA damage is detected, p53 halts the cycle via p21.
Team Members: Cyclin B, CDK1 (also called CDC2), Wee1 kinase, Cdc25 phosphatase, ATM/ATR proteins
Objective: Ensure DNA is fully replicated and undamaged before entering mitosis
Modus Operandi: Cyclin B binds CDK1 to form MPF (Maturation Promoting Factor). If DNA damage is detected, ATM/ATR activate Chk1/Chk2 → inhibit Cdc25 → CDK1 stays inactive → Mitosis is delayed. Once DNA is verified, Cdc25 activates CDK1 → Cell enters mitosis.
Team Members: MAD2, BUB1, CDC20, APC/C (Anaphase-Promoting Complex/Cyclosome)
Objective: Ensure all chromosomes are correctly attached to the spindle before separation
Modus Operandi: Unattached kinetochores recruit MAD2/BUB1 → inhibit CDC20 → blocks APC/C activation. Once all chromosomes are properly attached, MAD2 is released → CDC20 activates APC/C → APC degrades securin → Separase is activated → Cohesins are cleaved → Chromosomes segregate into daughter cells.
Cell cycle checkpoints ensure that:
- 🧬 Damaged or incomplete DNA is not passed to daughter cells
- ⚖️ Chromosome number remains stable
- 🔒 Errors trigger arrest or apoptosis, preventing tumor formation
- 📈 Fidelity of cell division is maintained in multicellular organisms
Answer: ❌ No, those terms (PPC, MPC, TPC) do not exist in biology.
Only APC/C (Anaphase-Promoting Complex/Cyclosome) is a real and essential molecular complex involved in mitosis.
The terms “PPC,” “MPC,” or “TPC” are not used in scientific literature or cell biology.
✅ What Exists Then? Here’s what you should know stage-wise, along with the key molecules involved:
Events: Chromosomes condense, nucleolus disappears, spindle fibers begin to form, centrosomes move to poles.
Molecular Control: Cyclin B–CDK1 complex (aka MPF = Maturation Promoting Factor) becomes activated. MPF triggers nuclear envelope breakdown, chromosome condensation (via condensins), and spindle formation.
Checkpoint: No specific complex like “PPC”, but G2–M checkpoint ensures readiness before this stage starts.
Events: Chromosomes align at the metaphase plate, spindle fully formed.
Molecular Control: Still driven by active MPF. Spindle Assembly Checkpoint (SAC) ensures all kinetochores are attached.
Key Proteins: MAD2, BUB1, CDC20 hold APC/C in check until all chromosomes are properly aligned.
Events: Sister chromatids separate and move to opposite poles.
Molecular Control: APC/C (Anaphase-Promoting Complex/Cyclosome) is activated by CDC20. APC/C degrades securin → activates separase → cleaves cohesin → chromatid separation.
Checkpoint: This is the checkpoint-regulated phase with a named complex: APC/C.
Events: Chromosomes decondense, nuclear envelope reforms, spindle disassembles.
Molecular Control: APC/C degrades Cyclin B → inactivates CDK1 → enables telophase and cytokinesis.
Note: No “TPC” exists, but APC/C still plays a vital role.
Events: Division of the cytoplasm to form two daughter cells.
Key Molecules: Actin filaments, Myosin II
Function: Completes cell division process, producing two genetically identical daughter cells.
| Mitosis Phase | Key Events | Main Regulator(s) | Named Complex |
|---|---|---|---|
| Prophase | Chromosome condensation, spindle formation | MPF (Cyclin B–CDK1) | ❌ No PPC |
| Metaphase | Chromosomes align at equator | MPF + SAC control | ❌ No MPC, SAC active |
| Anaphase | Sister chromatids separate | APC/C + CDC20 | ✅ APC/C |
| Telophase | Nuclear envelope reforms, chromosomes relax | APC/C-mediated CDK1 inactivation | ❌ No TPC |