A 28-year-old woman with stage IB1 cervical squamous cell carcinoma undergoes radical hysterectomy. HPV-16 E6 protein is detected in the tumor. What is the mechanism by which HPV E6 protein promotes malignant transformation in cervical epithelium?
- A E6 binds and mediates ubiquitin-proteasome degradation of TP53, preventing p53-mediated apoptosis and cell cycle arrest in response to DNA damage ✓
- B E6 binds pRb (retinoblastoma protein), releasing E2F transcription factor to drive S-phase entry
- C E6 activates telomerase by directly binding the TERT promoter, extending replicative lifespan
- D E6 competitively inhibits MDM2 binding to p53, paradoxically stabilizing a mutant gain-of-function p53 protein
Correct answer: A. E6 binds and mediates ubiquitin-proteasome degradation of TP53, preventing p53-mediated apoptosis and cell cycle arrest in response to DNA damage
Explanation
HPV E6 (high-risk types 16, 18) forms a trimeric complex with the ubiquitin ligase E6-AP (UBE3A), which then ubiquitinates TP53 for proteasomal degradation. This eliminates p53-mediated surveillance of DNA damage, allowing cells with genomic instability to survive and accumulate further mutations. E7 (not E6) binds and inactivates pRb. While HPV can induce telomerase, E6's primary oncogenic function is TP53 degradation. The interaction of E6 with E6-AP (an HECT-domain E3 ligase) is the molecular basis of HPV-mediated carcinogenesis.
Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
Written and medically reviewed by the StethoPrep medical team.