RB1 acts as the 'guardian of the cell cycle.' A retinoblastoma develops in a child with germline RB1 mutation. When the second allele is somatically inactivated, pRb loss promotes entry into S-phase by:

• A Directly activating CDK4 kinase activity through allosteric binding
• B Sequestering p21 and p27 CKIs away from the cyclin D-CDK4/6 complex
• C Releasing E2F transcription factors from pRb-E2F repressor complexes, permitting transcription of S-phase genes ✓
• D Promoting MDM2-mediated ubiquitination and degradation of p53

Explanation

In its hypophosphorylated (active) state, pRb binds and sequesters E2F transcription factors, keeping them inactive and blocking transcription of genes needed for S-phase entry (e.g., cyclin E, DHFR, thymidine kinase). Cyclin D-CDK4/6 complexes phosphorylate pRb, releasing E2F, which then drives the G1→S transition. When pRb is absent (both alleles lost), E2F is constitutively free and the cell cycle brake is permanently removed. MDM2-p53 interaction is a separate checkpoint; p21/p27 sequestration by oncoproteins is a different mechanism used by, e.g., viral proteins like HPV E7.

Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.