🧠 p53 Explained for USMLE Step 1: Tumor Suppression, Cell Cycle Arrest, and Li-Fraumeni Syndrome

The p53 protein is often called the “guardian of the genome.” It’s one of the most tested tumor suppressor genes on Step 1 because of its role in DNA damage sensing, cell cycle regulation, and apoptosis.

In this post, we’ll explain:

• What p53 does molecularly

• What happens when it’s mutated

• Which cancers it’s linked to

• And how it shows up on Step 1 clinical vignettes

🧬 What Is p53?

• Encoded by the TP53 gene on chromosome 17

• Normally kept at low levels in cells

• Activated in response to:

  • DNA damage

  • Hypoxia

  • Oncogene overexpression

🧪 Core Function:
p53 stops the cell cycle at the G1 → S checkpoint by inducing p21, which inhibits CDK2/cyclin E

If damage is irreparable → p53 triggers apoptosis

🔁 p53 Function Summary Table

Trigger	p53 Action	Downstream Effect
DNA damage	↑ p53 expression	Activates p21 → Cell cycle arrest
Oncogenic stress	Activates BAX, PUMA	Induces apoptosis
Hypoxia	Stabilized p53 expression	Replication paused to prevent mutation

⚠️ What Happens When p53 Is Mutated?

• Cell keeps dividing even with DNA errors

• Apoptosis is suppressed

• Genome instability increases

• Accelerated tumor formation

🔬 p53 mutations are found in >50% of human cancers

🧬 Li-Fraumeni Syndrome

Inheritance	Autosomal dominant
Gene	TP53 (germline mutation)
Classic Cancers	Sarcomas, Breast cancer, Brain tumors, Leukemia, Adrenocortical carcinoma
Clinical Tip	Multiple family members with different cancers at a young age = red flag 🚩

🧠 USMLE Step 1 Clues to Watch For

A 14-year-old with osteosarcoma and a family history of breast cancer, glioblastoma, and leukemia. Genetic testing reveals a germline mutation in a tumor suppressor.

✅ Answer: TP53 → Li-Fraumeni Syndrome

💡 Mnemonics to Master

“p53 = Police 53”

• Stops the cycle

• Arrests bad cells

• Kills unfixable offenders (apoptosis)

“Li-Fraumeni = Lethal Family Mutations”

🔬 p53 vs Rb: Know the Difference

Feature	p53	Rb
Checkpoint	G1/S	G1/S
Function	Senses damage and induces p21 for cell cycle arrest or apoptosis	Binds and inhibits E2F transcription factor to prevent premature S-phase entry
Cancer Link	Li-Fraumeni Syndrome (TP53 mutation)	Retinoblastoma (RB1 gene mutation)

🎯 Call-To-Action

Want more regulatory checkpoints and cancer mutation charts?

🧠 Explore the KOTC Adaptive Qbank and visual-packed classroom tools:
🔗 https://kingofthecurve.org/trial-sessions

🎓 Unlock lifetime access to our full oncology + genetics visual database:
🔗 https://kingofthecurve.org/free-lifetime

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