The Restriction Point: Rb and E2F

Late in G1 sits the restriction point (R). Before R, a cell needs continuous growth-factor signals to keep going. After R, it commits to finishing the cycle even if signals vanish. Most cancers have broken this single gate.

The gatekeeper is the retinoblastoma protein (Rb). Unphosphorylated Rb binds the transcription factor E2F and keeps it silent. E2F controls genes needed for S phase: cyclin E, DNA polymerase, thymidine kinase and more.

Growth signals raise cyclin D, which activates CDK4/6. These phosphorylate Rb partially, loosening its grip on E2F. Released E2F turns on cyclin E, which activates CDK2, which phosphorylates Rb further — a positive feedback loop. Within a short window, Rb is fully phosphorylated, E2F is fully free, and the cell is committed.

This all-or-none behavior is why the restriction point acts like a switch, not a dimmer.

Tumors disable the Rb pathway in almost every possible way: deleting RB1 itself (retinoblastoma, small-cell lung cancer), deleting p16, amplifying cyclin D1 (breast, head and neck cancers), or overactivating CDK4.

Viruses do it too. The HPV E7 oncoprotein binds Rb and releases E2F — one reason high-risk HPV causes cervical and throat cancers.