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Molecular mechanisms underlying RB protein function

Nature Reviews Molecular Cell Biology volume 14, pages 297–306 (2013)Cite this article

Subjects

Key Points

  • RB is a central regulator of cell cycle entry, and its function is disrupted in most human cancers.

  • RB is a modular protein, with three domains, and this structure allows it to function as an adaptor that nucleates several different protein complexes.

  • RB inhibits transcription by E2F transcription factors to prevent cell cycle advancement.

  • Stabilization of p27 expression through RB inhibition of S phase kinase-associated protein 2 (SKP2) inhibits cell cycle progression. Through this mechanism, RB regulates cyclin-dependent kinase (CDK) activity independently of transcription.

  • RB is required for loading condensin II and cohesin complexes onto mitotic chromosomes. In the absence of this function, defective chromosome condensation and congression in mitosis lead to aneuploidy.

  • RB uses an alternative interaction with E2F1 to regulate apoptosis separately from E2F-dependent control of the cell cycle.

Abstract

Inactivation of the RB protein is one of the most fundamental events in cancer. Coming to a molecular understanding of its function in normal cells and how it impedes cancer development has been challenging. Historically, the ability of RB to regulate the cell cycle placed it in a central role in proliferative control, and research focused on RB regulation of the E2F family of transcription factors. Remarkably, several recent studies have found additional tumour-suppressor functions of RB, including alternative roles in the cell cycle, maintenance of genome stability and apoptosis. These advances and new structural studies are combining to define the multifunctionality of RB.

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Figure 1: RB is a multidomain protein with several distinct protein-binding surfaces.
Figure 2: Regulation of E2Fs by RB.
Figure 3: Transcription-independent regulation of cyclin-dependent kinases by RB.
Figure 4: Regulation of pericentromeric heterochromatin by RB.
Figure 5: Differential regulation of E2F1 in apoptosis.

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Acknowledgements

Research in the authors laboratories is supported by awards from the Canadian Institutes of Health Research (MOP89765 and MOP64253) and the Canadian Cancer Society Research Institute (2011-700720) to F.A.D, and the US National Institutes of Health (R01CA132685) and the American Cancer Society (RSG-12-131-01-CCG) to S.M.R. F.A.D is The Wolfe Senior Fellow in Tumour Suppressor Genes.

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Authors and Affiliations

  1. and Department of Biochemistry, London Regional Cancer Program, Children's Health Research Institute, Western University, London, N6A 4L6, Ontario, Canada

    Frederick A. Dick

  2. Department of Chemistry and Biochemistry, University of California, Santa Cruz, 95064, California, USA

    Seth M. Rubin

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Correspondence to Frederick A. Dick or Seth M. Rubin.

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DATABASES

Protein Data Bank

2QDJ

1GUX

1N4M

2AZE

FURTHER INFORMATION

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Glossary

Cyclin

A family of proteins that activate cyclin-dependent kinases and whose stability is cell-cycle regulated.

CDK

(Cyclin-dependent kinase). A family of kinases that are activated by cyclins.

E2F

(E2-binding factor). A family of cell-cycle regulated transcription factors.

Pocket

A region in RB-family proteins that was originally determined to bind to viral oncoproteins, such as SV40 TAg.

Differentiation-related polypeptide

(DP). The E2F dimerization partner.

Pocket proteins

RB-family proteins, defined by their possession of the central 'pocket' domain.

p27

An inhibitor of cyclin-dependent kinase activity.

F box protein

A protein containing the F box domain, an approximately 50-amino acid motif that facilitates protein–protein interactions.

S phase kinase-associated protein 2

(SKP2). An adaptor protein that recruits p27 to the SKP–cullin–F box E3 ligase complex.

APC/C

(Anaphase-promoting complex; also known as the cyclosome). An E3 ubiquitin ligase.

Merotelic

When multiple microtubules, emanating from opposite spindle poles, simultaneously bind to a single kinetochore.

Aneuploidy

An abnormal number of chromosomes in a cell.

Centromere

A constricted region of a chromosome that interacts with kinetochores and is the attachment point for spindle microtubules.

Condensin II

A protein complex made up of seven protein subunits that create a ring structure to link and supercoil DNA strands.

Cohesin

A ring-structured protein complex similar to the condensins that creates cohesion between replicated, homologous DNA strands and regulates their separation during cell division.

Pericentromere

A repetitive chromosomal region adjacent to the centromere.

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Dick, F., Rubin, S. Molecular mechanisms underlying RB protein function. Nat Rev Mol Cell Biol 14, 297–306 (2013). https://doi.org/10.1038/nrm3567

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