RB, p53 and APC genes and their roles in tumor development

1. Tumor suppressor genes

Encode proteins that inhibit proliferation; require two hits (loss of both alleles) for loss of function.

2. RB — the G1→S gatekeeper

• Controls the G1→S checkpoint. Active = hypophosphorylated Rb binds E2F, blocking S-phase entry.
• Cyclin D-CDK4/6 phosphorylates Rb → inactive (hyperphosphorylated) → E2F released → S-phase.
• Loss of RB → E2F constitutively active → uncontrolled proliferation.
• Diseases: retinoblastoma (eye), osteosarcoma, breast, SCLC, bladder.

3. p53 — “guardian of the genome”

• Most commonly mutated gene in human cancer (>70% defective in some pathway).
• Unstressed: bound to MDM2 → degraded. DNA damage → p53 stabilized → activates:
  • p21 (CDK inhibitor) → blocks Rb phosphorylation → G1 arrest (quiescence/senescence).
  • GADD45 → DNA repair.
  • Bax/PUMA → apoptosis if damage is irreparable.
• Loss → no arrest/repair/apoptosis → mutations accumulate. Li-Fraumeni (germline); inactivated by HPV E6.

4. APC — Wnt/β-catenin brake

• Part of the destruction complex (APC, GSK3β, Axin) that degrades β-catenin when Wnt is off.
• Loss of APC → β-catenin accumulates → nucleus → TCF → transcribes MYC, cyclin D1 → proliferation.
• Disease: FAP (familial adenomatous polyposis) — hundreds of colonic polyps, inevitable colorectal carcinoma; the first hit in the colon adenoma-carcinoma sequence.

💡 High-yield: RB — hypophosphorylated Rb binds E2F (G1-S); cyclin D-CDK4 releases it; loss → retinoblastoma. p53 — MDM2-controlled; p21 (arrest), GADD45 (repair), Bax (apoptosis); most mutated gene, Li-Fraumeni, HPV E6. APC — degrades β-catenin; loss → FAP / colon adenoma-carcinoma sequence. All need two hits.