Inhibitory mechanisms of tumor suppressor genes and role in carcinogenesis

1. Concept

Tumor suppressor genes encode proteins that inhibit proliferation (the “brakes”). Unlike oncogenes, they are recessive at the cellular level — both alleles must be lost (Knudson two-hit hypothesis) before function is lost (loss of heterozygosity, LOH).

2. Mechanisms of inactivation

1. Deletion of one allele.
2. Point mutation — nonsense (stop) or missense.
3. Epigenetic silencing — promoter hypermethylation.
4. Transdominant (dominant-negative) — mutant protein complexes with and inactivates the normal one.
5. Haploinsufficiency — one functional allele makes too little protein.

3. Two genetic pathways

• Hereditary cancer — one defective allele inherited in germline; only 1 somatic “hit” needed → earlier/multifocal tumors.
• Sporadic cancer — two normal alleles inherited; 2 somatic hits needed.

4. Key examples

Gene	Normal function	Loss → disease
RB	G1→S checkpoint; hypophosphorylated Rb binds E2F. Cyclin D-CDK4 phosphorylates Rb → releases E2F → S-phase	Retinoblastoma; also breast, SCLC, bladder
p53	“Guardian of the genome”: DNA damage → p21 → arrest; GADD45 → repair; Bax/PUMA → apoptosis. Held by MDM2 when unstressed	>70% of cancers; Li-Fraumeni; inactivated by HPV E6
APC	Destruction complex degrades β-catenin (Wnt off)	β-catenin accumulates → TCF → MYC/cyclin D1 → FAP / colon adenoma-carcinoma sequence

💡 High-yield: Tumor suppressors = brakes; need two hits (LOH). Inactivation: deletion, mutation, promoter hypermethylation, dominant-negative, haploinsufficiency. RB (E2F/G1-S), p53 (most commonly mutated, MDM2/p21/Bax), APC (β-catenin/Wnt → FAP). Hereditary = 1 hit needed; sporadic = 2 hits.