Cellular mechanisms of tumour suppression by the retinoblastoma gene

Abstract

The retinoblastoma (RB) tumour suppressor gene is functionally inactivated in a broad range of paediatric and adult cancers, and a plethora of cellular functions and partners have been identified for the RB protein. Data from human tumours and studies from mouse models indicate that loss of RB function contributes to both cancer initiation and progression. However, we still do not know the identity of the cell types in which RB normally prevents cancer initiation in vivo, and the specific functions of RB that suppress distinct aspects of the tumorigenic process are poorly understood.

Figure 1 |. RB is a transcriptional co-factor and an adaptor protein that can function through at least four different types of protein interaction.

a | Classically, RB (retinoblastoma) binds to E2F transcription factors and recruits them away from their target genes. b | Alternatively, RB is recruited to the promoter of target genes by E2F and inhibits their transactivation activity and further recruits chromatin remodelling complexes (including HDAC (histone deactylase), DNMT1 (DNA methyltransferase 1), HP1A (heterochromatin protein 1A) and SUV39H1) to repress transcription. c | RB is a transcriptional co-factor for non-E2F transcription factors or other co-factors, such as the HIF1α (hypoxia-induced factor 1α), MYOD and SP1 transcription factors. d | RB serves as a non-chromatin-associated protein adaptor: illustrated is one example of RB acting to recruit APC/C (anaphase promoting complex/cyclosome) and SKP2 (S-phase kinase-associated protein 2) to the same complex, promoting SKP2 degradation.

Figure 2 |. Functions of RB that are potentially involved in the prevention of cancer initiation in adult cells.

Adult tissues consist of stem cells that are able to produce cycling progenitor cells; these progenitors produce cells that eventually undergo terminal differentiation. In each of these cell types, RB (retinoblastoma) controls distinct cellular processes, which might be partly E2F-dependent and partly E2F-independent, and might involve extensive chromatin remodelling. Loss of RB will have different effects in each cell type. Although the control of the G1–S checkpoint is the most studied function of RB, the abrogation of this function might only be crucial under specific conditions, such as during tumour initiation from cycling progenitor cells.

Figure 3 |. Overview of the numerous RB binding partners and transcriptional targets that might mediate its tumour suppressor ability.

Presence of RB (retinoblastoma) might prevent tumour formation by inducing differentiation, controlling cell-cycle arrest, maintaining genomic stability and inducing senescence in response to oncogenic stresses. Furthermore, the absence of RB has been associated with increased angiogenesis and metastasis, although the mediators of these functions are less well understood. Surprisingly, presence of RB has a pro-survival function because of its inhibition of cell death through apoptosis and, potentially, autophagy. This function, shown in green, might be necessary for early tumour cell survival in some contexts. This figure depicts a simplified representation of the potential role of RB in tumour suppression. Each function is illustrated with some of the key protein binding partners and transcriptional targets that might be necessary for the function, but they are not meant to be comprehensive. APAF1, apoptotic peptidase activating factor 1; BNIP3, BCL2-interacting protein 3; CDH1, cadherin 1; DNMT1, DNA methylatransferase 1; HIF1α, hypoxia-induced factor 1α; PCNA, proliferating cell nuclear antigen; VEGF, vascular endothelial growth factor.