Retinoblastoma protein (RB)–E2F transcription factor interface (RB–E2F interface)

The Retinoblastoma protein (RB)–E2F transcription factor interface is a fundamental regulatory node in the mammalian cell cycle, specifically controlling the transition from the G1 to the S phase (UniProt P06400). In its hypophosphorylated state, the Retinoblastoma protein (RB) binds to the transactivation domain of E2F transcription factors, effectively silencing the expression of genes necessary for DNA replication and cell cycle progression (Dick & Rubin, 2013). This interaction is typically regulated by the phosphorylation of RB by Cyclin-Dependent Kinases (CDK4/6), which triggers the release of E2F and allows the cell to proceed into the S phase (Sherr, 1996). Dysregulation of this interface, often through RB1 mutations or upstream hyperactivation of CDKs, is a nearly universal feature of human cancers, leading to uncontrolled cellular proliferation (Hanahan & Weinberg, 2011). Therapeutic strategies targeting this interface aim to either mimic the inhibitory effect of RB on E2F or disrupt the interaction in specific contexts to induce apoptosis or senescence in malignant cells (Topacio et al., 2019). While direct small-molecule inhibitors of the RB–E2F interface are largely in the preclinical stage, they represent a promising approach to bypass resistance to upstream CDK4/6 inhibitors (Kent & Leone, 2019).

Other names

pRb-E2F interactionRB1-E2F complexRetinoblastoma-E2F protein-protein interaction

Inhibition of the protein-protein interaction between the Retinoblastoma protein (RB) and E2F transcription factors to modulate the expression of genes required for the S-phase of the cell cycle (Dick & Rubin, 2013).