Oncogenic transformation of cells can induce the cyclin-dependent kinase inhibitor, p16, which leads to hypophosphorylation and activation of retinoblastoma (Rb). Rb is capable of causing permanent growth arrest, which may underlie its role as a tumor suppressor. We show that repression by Rb at E2F target gene promoters involves the establishment of a stable repressor complex that is not displaced by the overexpression of E2F-1. Rather than displacing Rb, excess E2F-1 instead recruits more Rb, leading to direct transcriptional repression. In contrast, the Rb family members, p130 and p107, which have not been demonstrated to be tumor suppressors, bind preferentially to target promoters in the absence of growth factors and in proliferating cells, respectively, and these repressor complexes are displaceable by E2F-1. Heterochromatin protein 1 (HP1), which interacts with Rb, is associated with these distinct repressor complexes and follows a similar pattern of stability/displaceability. Efficient growth arrest by p16/Rb is dependent on histone H3 lysine 9 methylation, which provides a binding site for HP1. We propose that these differences in the stability of repressor complexes at promoters may, in part, underlie the different roles of Rb vs p130 and p107 in cell cycle regulation and tumor suppression.
- Repressor complex stability
- Tumor suppression