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  • Review Article
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Oncogenes and tumour suppressors take on centrosomes

Nature Reviews Cancer volume 7, pages 911–924 (2007)Cite this article

Key Points

  • As core components of spindle poles, centrosomes have a key role in directing the formation of bipolar mitotic spindles, which is crucial for accurate segregation of chromosomes during cytokinesis.

  • Numeral and functional abnormalities of centrosomes result in mitotic spindle defects, leading to chromosome segregation errors, and are the major causes of chromosome instability in cancer, which accelerates the step-wise tumour progression.

  • Several oncogenic and tumour-suppressor proteins are found to be involved in the regulation of centrosome duplication and function, and mutations of those proteins result in mitotic defects that are associated with numeral and functional abnormalities of centrosomes.

  • The centrosome regulation activities of these oncogenic and tumour-suppressor proteins are crucial parts of their overall oncogenic, tumour-suppressing potential.

Abstract

Chromosome instability, which is equated to mitotic defects and consequential chromosome segregation errors, provides a formidable basis for the acquisition of further malignant phenotypes during tumour progression. Centrosomes have a crucial role in the formation of bipolar mitotic spindles, which are essential for accurate chromosome segregation. Mutations of certain oncogenic and tumour-suppressor proteins directly induce chromosome instability by disrupting the normal function and numeral integrity of centrosomes. How these proteins control centrosome duplication and function, and how their mutational activation and/or inactivation results in numeral and functional centrosome abnormalities, is discussed in this Review.

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Figure 1: Structure and function of centrosomes.
Figure 2: The centrosome-duplication cycle.
Figure 3: Mitotic defects associated with numeral abnormalities of centrosomes and the consequential destabilization of chromosomes.
Figure 4: Mitotic defects associated with abnormal function and behaviour of the centrosome.
Figure 5: Loss of p53-dependent centrosome reduplication in cells arrested by exposure to DNA synthesis inhibitors.
Figure 6: Centrosome amplification in cells arrested by the G2/M checkpoint in response to DNA damage occurs efficiently in the absence of p53.

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Acknowledgements

I apologize for not being able to cite many important studies owing to space limitations. Preparation of this article is supported in part by grants from the National Institutes of Health (Bethesda, Maryland, USA).

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  1. Molecular Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, 33612, Florida, USA

    Kenji Fukasawa

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Supplementary information

Supplementary information S1 (Table)

A complete list of cancer-associated proteins which are involved in the control numeral integrity of centrosomes, centrosome duplication, and centrosome function/behavior. (PDF 375 kb)

Glossary

Pericentriolar material

(PCM). Aggregates of many different proteins surrounding the paired centrioles. The protein composition of PCM is dynamic: some proteins are permanent residents of the centrosome, whereas some localize to the centrosome in a manner that is specific to the cell-cycle stage.

Mitotic spindle

The term commonly and synonymously used for describing the dynamic mitotic spindle apparatus.

Aneuploid

Having a change in the number of chromosomes. It should be distinguished from polyploid (presence of more than two homologous sets of chromosomes).

Centrosome amplification

The generation of more than two centrosomes, primarily resulting from deregulated centrosome duplication — duplication of centrosomes more than once in a single cell cycle.

Checkpoint

The control mechanisms that ensure the fidelity of cell division in eukaryotic cells by monitoring whether the processes at each phase of the cell cycle have been accurately completed before progression into the next phase.

Polyploid

Having more than two homologous sets of chromosomes (for example, triploid (three sets), tetraploid (four sets)).

Centrosome clustering

The phenomenon of amplified centrosomes clustering at two opposing poles, in which dynein, a multi-subunit microtubule-based motor protein that moves towards the minus ends of microtubules, has been shown to have a role.

Centrosome maturation

A process taking place in S and G2 phases that establishes the microtubule nucleation or anchoring activities of centrosomes required for the formation of mitotic spindles by recruiting critical pericentriolar material components.

Mitotic catastrophe

A form of (apoptotic) cell death resulting from abnormal mitosis due to DNA damage.

Hydroxyurea

A potent ribonucleotide reductase inhibitor, hydroxyurea exposure results in deprivation of dNTP, leading to inhibition of S-phase entry and S-phase progression.

γ-Tubulin

A major centrosomal protein that functions in the microtubule nucleation or anchoring at the centrosome through forming a protein complex with several other proteins, known as γ-tubulin ring complex (γ-TuRC). γ-TuRC is believed to function as a template for microtubules to grow.

Poly(ADP-ribosyl)ation

One of the major post-translational modifications of proteins, catalysed by the poly(ADP-ribose) polymerase family of proteins. The attachment of ADP-ribose polymers adds a high negative charge, affecting the activities of the target proteins.

Kinesin

A family of microtubule-based motor proteins that move towards the plus ends of microtubules.

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Fukasawa, K. Oncogenes and tumour suppressors take on centrosomes. Nat Rev Cancer 7, 911–924 (2007). https://doi.org/10.1038/nrc2249

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