Cell Growth Regulation

Question 1

What are Growth Factors, Cytokines, and Interleukins?

What is Paracrine, Autocrine, and Endocrine release?

Answer 1

• Proteins that stimulate proliferation/mitosis (mitogens) and maintain survival, stimulate differentiation and inhibit proliferation and induce apoptosis
• Paracrine (released locally), Autocrine (released locally and activates itself), Endocrine (released into blood)

Question 2

MITOSIS:
Outline the cell cycle

Give 2 examples of S-phase active drugs. How do they work?

Give 2 examples of M-phase active drugs. How do they work?

Of these 4 drugs above, which are used in cancer treatment?

Where are the 3 Checkpoints in the cell cycle? What does each check for?

What is important about the G1 phase?

Answer 2

• • Interphase - G1 → S → G2
  • Prophase - Microtubule Spindle forms and Centrioles migrate to poles
  • Metaphase - Chromosomes line up on equator
  • Anaphase - Chromatids separate
  • Telophase - Daughter nuclei form
  • Cytokinesis
• • 5-Fluorouracil - Analogue of thymidine which blocks thymidylate synthesis
  • Bromodeoxyuridine - Analogue of thymidine which is incorporated into DNA and detected by antibodies to identify cells that have passed through S-phase
• • Colchicine and Vinca Alkaloids - Stabilises free tubulin to prevent microtubule polymerisation = Arrests mitotic cells
  • Paclitaxel - Stabilises microtubules to preventing de-polymerisation
• 5-Fluorouracil, Vinca Alkaloids, and Paclitaxel
• 1. Restriction point (at end of G1 phase) - Checks for DNA damage, Cell size, and Nutrient stores
     
     2. G2-Mitosis Transition - Checks for Complete DNA replication and DNA damage
     3. Metaphase-Anaphase Transition - Checks for correct Chromosome attachment to spindle
• Is when the cell is most responsive to Growth factors - Main time of control for cell growth

Question 3

CYCLIN-DEPENDENT KINASE (CDK):
What does this do?

What are the 2 subunits involved in it?

What does an Active Cyclin-CDK complex do?

What regulates Cyclin-CDK activity?

How Growth Factors affect Cyclin expression?

e. g. For Retinoblastoma (RB) protein, how are CDK’s used?
- ——————–

Cyclin-Dependent Kinase Inhibitors (CKI):
1. CDK/Kinase Inhibitory Protein (CIP/KIP) - What does this do?
→ What stimulates these weakly and strongly?

2. Inhibitor of Kinase 4 (INK4) - What does this do?
   → What stimulates these?

Answer 3

• Controls CELL CYCLE PROGRESSION
• • CDK - Catalytic subunit
  • Cyclin - Regulatory subunit
• Phosphorylates substrates
• CDK INHIBITORS, Gene expression (cyclical synthesis) and destruction (by proteasome), Post-translational modification by phosphorylation/dephosphorylation
• Induces Cyclin expression
• RB protein binds to E2F, preventing it from stimulating S-phase protein expression
  o Cyclin-CDK complex phosphorylates RB protein, which causes it to release the E2F for S-phase protein expression
  ———————

1. Inhibits all other Cyclin-CDK complexes (Late G1, G2 and M)
   → Weakly by TGF- β and STRONGNLY by DNA DAMAGE
2. Specifically inhibits G1 CDKs
   → TGF-β

Question 4

DNA damage:
When is it detected?

What does the detection of DNA damage lead to?
→ What are the outcomes of this?

Answer 4

• Checkpoints 1/2
• Kinase activation and phosphorylation of TP53 Tumor Suppressor Gene
  → o Expression of CKI (Inhibitors) to arrest cell cycle
  o DNA repair
  o Apoptosis (if repair isn’t possible)