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

Cyclin D1 is a critical regulatory protein that controls the transition from the G1 to the S phase of the cell cycle by forming a complex with cyclin-dependent kinases 4 and 6 (CDK4/6) (UniProt P24385). The primary function of this complex is to phosphorylate the Retinoblastoma protein (Rb), a tumor suppressor that normally sequesters E2F transcription factors (UniProt P06400). The physical interaction between Cyclin D1 and Rb is a necessary step for this phosphorylation, which leads to the release of E2F and the activation of genes required for DNA synthesis (Sherr, Science 1996). In many cancers, such as ER-positive breast cancer and mantle cell lymphoma, Cyclin D1 is overexpressed, causing constitutive Rb phosphorylation and driving uncontrolled cell growth (Musgrove et al., Nat Rev Cancer 2011). While current clinical strategies utilize CDK4/6 inhibitors like palbociclib to block the kinase activity of the complex, the Cyclin D1–Rb protein-protein interaction (PPI) itself is an attractive therapeutic target (O'Leary et al., Nat Rev Clin Oncol 2016). Directly disrupting this PPI could potentially overcome resistance to ATP-competitive inhibitors and provide a more targeted approach for Rb-proficient tumors (Dick et al., Nat Rev Cancer 2013). Research into small molecules and peptidomimetics that interfere with the binding interface between Cyclin D1 and Rb is ongoing to develop next-generation cell cycle inhibitors.

Other names

CCND1-RB1 interactionCyclin D1-pRb complexCyclin D1-Rb bindingCyclin D1-CDK4/6-Rb axis

Disruption of the physical binding between Cyclin D1 and the Retinoblastoma protein (Rb) to prevent Rb phosphorylation, thereby maintaining Rb-mediated repression of E2F transcription factors and inducing G1 cell cycle arrest (Sherr, Science 1996; Musgrove et al., Nat Rev Cancer 2011).