Cyclin D1–Retinoblastoma protein interface (Cyclin D1–Rb PPI)

The Cyclin D1–Retinoblastoma protein (Rb) interface is a pivotal protein-protein interaction (PPI) that regulates the G1-to-S phase transition in the eukaryotic cell cycle (UniProt P24385, P06400). Cyclin D1 acts as a regulatory subunit that binds to the pocket domain of the Rb tumor suppressor, facilitating its phosphorylation by cyclin-dependent kinases 4 and 6 (CDK4/6) (PubMed: 25660493). This phosphorylation inactivates Rb, causing the release of E2F transcription factors that drive the expression of genes necessary for DNA replication. Dysregulation of this interface, often through Cyclin D1 overexpression, is a hallmark of various malignancies, including breast cancer and mantle cell lymphoma (PubMed: 31431350). While current FDA-approved therapies like Palbociclib and Abemaciclib target the ATP-binding site of CDK4/6, the Cyclin D1–Rb interface is an emerging target for direct PPI inhibitors. These novel agents aim to disrupt the physical association between the two proteins, thereby maintaining Rb in its active, hypophosphorylated state to induce cell cycle arrest and inhibit tumor growth (PubMed: 31431350, 25660493).

Other names

Cyclin D1–RB1 interfaceCCND1–pRb interactionCyclin D1–RB1 protein-protein interactionCyclin D1–Retinoblastoma protein complex

Direct disruption of the protein-protein interaction between Cyclin D1 and the Retinoblastoma protein (Rb) to prevent CDK4/6-mediated phosphorylation of Rb, thereby maintaining Rb in its active, growth-suppressive state and inducing G1 cell cycle arrest (PubMed: 31431350).