The retinoblastoma tumour suppressor in development and cancer

Abstract

Since its discovery, the retinoblastoma (RB) tumour-suppressor protein has been a focal point of cancer research. Accumulating evidence indicates a complex role for RB in cell proliferation, differentiation and survival. To further complicate matters, proteins that are related to RB have redundant as well as antagonistic functions. Recent studies of knockout mice and cells that lack one or more of these proteins have begun to clarify their various context-specific functions and the unique activity of this tumour suppressor.

Retinoblastoma family genes

“…As shown in Figure 3, while Rb preferentially binds to E2Fs 1-4, p107 and p130 predominantly bind to E2Fs 4 and 5 (Classon and Harlow, 2002). The preferential binding of activating E2Fs by Rb but not by p107 or p130 potentially underlies the observation that only Rb mutations are frequently detected in cancers.…”

“…This is similar to RNAi knock-down of dE2F1 in Drosophila SL2 cells , supporting the notion of a conserved role for the activating E2F proteins. Although simplified models suggest that the Rb/E2F complexes present during quiescence or G0 are replaced with free E2Fs at the G1/S transition, the actual composition of these complexes appears to vary with the cell cycle (Classon and Harlow, 2002;Bracken et al, 2004). In quiescent cells, p130 is the main pocket protein in complex with the inhibitory E2Fs, while in cycling cells it is replaced by p107/E2F 4 in G0/G1 phases and by Rb/E2F 1-3 complexes in S phase (Shirodkar et al, 1992).…”

Lysine methylation regulates the pRb tumour suppressor protein

“…One of the properties of pRb that influences differentiation relates to the need to exit the cell cycle before differentiation can occur, and the incompatibility between proliferation and differentiation (Chen and Wang, 2000;Classon and Harlow, 2002;Huh et al, 2004;van den Heuvel and Dyson, 2008). Thus, derivatives of pRb that exhibit compromised cell cycle arrest activity, similar to K873A, might be expected to possess defective differentiation-inducing activity, reflecting incomplete cell cycle exit rather than a deficit in a differentiation activity per se.…”

“…Consequently, genes required for entry into S-phase are no longer expressed and cells fail to undergo cell cycle progression. In addition to cell cycle control, pRb activity is intimately connected with other types of cell fate,, including differentiation, senescence and apoptosis (Classon and Harlow, 2002;Giacinti and Giordano, 2006). For example, Rb À/À mice exhibit embryonic lethality resulting from cell autonomous and non-cell autonomous effects, causing a lack of cellular differentiation and increased levels of apoptosis in diverse tissues (Clarke et al, 1992;Jacks et al, 1992;Lee et al, 1992;van den Heuvel and Dyson, 2008).…”

“…The tumour suppressor activity of pRb is regulated in part through post-translational modification, principally phosphorylation, directed by cyclin-dependent kinase Cdk (Classon and Harlow, 2002;Giacinti and Giordano, 2006). Serial phosphorylation events mediated by cyclin/Cdk complexes that occur during cell cycle progression inactivate pRb tumour suppressor activity, resulting in the release of E2F and cell cycle progression (Sherr, 2000).…”