Cell growth + division lecture 12

Question 1

p53

Answer 1

• Complete absence, mutated in both or just 1 allele
• 95% of mutations in DBD, x interact w/ DNA
• One of the most common genetic lesions
• TF, activated ds of stresses
• Can send cell to different response pathways, cell cycle arrest, apoptosis, senescence
• Li- Fraumeni
• Mdm2 inhibits (also oncogene, if ↑ activates p53), Arf sequesters Mdm2

Question 2

Activation of p53

Answer 2

1. DNA damage
   - Phosph by ATM protein kinase stab p53
   - ssDNA damage activates ATR
   - Chk1/2 → p53 phosph
2. Metabolic stress
   - Glucose depletion activates AMPK, phosph p53

Question 3

ds of p53

Answer 3

1. Cell cycle inhibition
   - p21 (inhibits G1 CDK)
   - 14-3-3 (sequesters Cdc25, x dephosphorylate CDK1)
2. Apoptosis
   - ↑ levels of p53 → apoptosis
   - Induces genes which ↑ ROS so ↑ Mit degradation + induces BH3 only PUMA
3. Angiogenesis
   - Thrombospondin

Question 4

Targeting p53 in cancer

Answer 4

• Normally hard to target
• Dominant -ve nature means can use small molecule inhibitor
• E.g. Nutlins inhibits Mdm2

Question 5

pRb + p53 link

Answer 5

1. p53-dependent G1/S arrest via p21 involves inhibitor of pRb phosph via Cdks
2. Dereg E2F activity induces p19ARF + p53-dpeendent apoptosis
3. P16INK4A + P19ARF = alternative reading frames of same locus (P16… = CDk4 inhibitor, p19.. stab p53