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Cellular mechanisms of tumour suppression by the retinoblastoma gene

Key Points

  • RB, the retinoblastoma protein, has been identified as a crucial tumour suppressor. It is believed to be directly or indirectly inactivated in nearly all human cancers.

  • RB has been demonstrated to bind to over one hundred protein partners and has been shown to mediate transcriptional regulation of hundreds of target genes. These protein partners and transcriptional targets are thought to mediate the numerous cellular functions of RB, including temporary and permanent cell cycle arrest, genomic stability, apoptosis and differentiation.

  • The cellular functions of RB, as well as a potential role in angiogenesis and metastasis, might contribute to its role as a tumour suppressor, but it is currently unknown which function is most critical. Distinct cellular functions of RB might contribute to its role in preventing tumour initiation versus its role in preventing tumour progression.

  • The function of RB that is crucial for tumour suppression might also depend on in which type of cell RB is lost — stem cell, progenitor or differentiated cell — as well as in which tissue.

  • In some contexts, presence of RB during earlier stages might be beneficial to tumour progression. Effects of post-translational modifications of RB on individual cellular functions might contribute to preference for a tumour to mutate RB or an upstream regulator.

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.

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Figure 1: RB is a transcriptional co-factor and an adaptor protein that can function through at least four different types of protein interaction.
Figure 2: Functions of RB that are potentially involved in the prevention of cancer initiation in adult cells.
Figure 3: Overview of the numerous RB binding partners and transcriptional targets that might mediate its tumour suppressor ability.

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Glossary

E2F transcription factors

Five members (E2F1–5) of a family of eight mammalian transcription factors that are transcriptional regulators, function as heterodimers with DP1–3 and have been shown to be regulated by direct binding to the pocket proteins.

Transcriptional co-factor

Protein that is recruited to promoters or enhancers of gene expression through binding to other proteins rather than to the DNA itself. Co-factors affect the transcriptional activity of transcription factors.

Cre–lox

Cre is a recombinase that specifically deletes DNA sequences flanked by lox sites.

Autophagy

A cellular stress response in which cellular proteins and organelles are digested and recycled by lysosomes in order to maintain active metabolism.

Aneuploidy

The occurrence of extra or missing chromosomes.

Pericentric heterochromatin

DNA regions around the centromeres of chromosomes that contain hypoacetylated and methylated histones, resulting in transcriptional silencing.

Senescence

Permanent cell cycle arrest, induced by cellular stresses and telomere shortening. Epigenetic changes prevent a mitogenic growth response, induce a distinct cellular morphology and promote expression of senescence-associated markers. Cells remain metabolically active.

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Burkhart, D., Sage, J. Cellular mechanisms of tumour suppression by the retinoblastoma gene. Nat Rev Cancer 8, 671–682 (2008). https://doi.org/10.1038/nrc2399

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