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Cell cycle, CDKs and cancer: a changing paradigm

Key Points

  • Cell cycle deregulation is a common feature of human cancer. Cancer cells frequently display unscheduled proliferation, genomic instability (increased DNA mutations and chromosomal aberrations) and chromosomal instability (changes in chromosome number).

  • The mammalian cell cycle is controlled by a subfamily of cyclin-dependent kinases (CDKs), the activity of which is modulated by several activators (cyclins) and inhibitors (Ink4, and Cip and Kip inhibitors). The activity of cell cycle CDKs is deregulated in cancer cells owing to genetic or epigenetic changes in either CDKs, their regulators or upstream mitogenic pathways.

  • Recent genetic studies indicate that CDK2, CDK4 and CDK6 are not essential for the mammalian cell cycle. Instead, they are only required for the proliferation of specific cell types. By contrast, CDK1 is essential for cell division in the embryo. Moreover, CDK1 is sufficient among the cell cycle CDKs for driving the cell cycle in all cell types, at least until mid gestation.

  • Constitutive and deregulated CDK activation may contribute not only to unscheduled proliferation but also to genomic and chromosomal instability in cancer cells. The alteration of the DNA damage and mitotic checkpoints frequently results in increased CDK activity that drives tumour cell cycles.

  • Emerging evidence suggests that tumour cells may also have specific requirements for individual CDKs. Therapeutic strategies based on CDK inhibition should take into consideration these specific requirements.

  • For instance, CDK4 is dispensable for mammary gland development, but is required for the development of mammary gland tumours initiated by specific oncogenes such as Erbb2, Hras or Myc depending on cellular context.

Abstract

Tumour-associated cell cycle defects are often mediated by alterations in cyclin-dependent kinase (CDK) activity. Misregulated CDKs induce unscheduled proliferation as well as genomic and chromosomal instability. According to current models, mammalian CDKs are essential for driving each cell cycle phase, so therapeutic strategies that block CDK activity are unlikely to selectively target tumour cells. However, recent genetic evidence has revealed that, whereas CDK1 is required for the cell cycle, interphase CDKs are only essential for proliferation of specialized cells. Emerging evidence suggests that tumour cells may also require specific interphase CDKs for proliferation. Thus, selective CDK inhibition may provide therapeutic benefit against certain human neoplasias.

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Figure 1: Comparison of the Saccharomyces cerevisiae cell cycle with the mammalian cell cycle, highlighting the major defects implicated in human cancer.
Figure 2: Genetic interrogation of the roles of cyclin-dependent kinases (CDKs) in the mammalian cell cycle.
Figure 3: An overview of key molecules involved in mitotic progression and chromosomal instability.

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Acknowledgements

This work was funded by grants from the Ministry of Science and Innovation (MICINN) (SAF2006-05186 to M.M. and SAF2006-11773 to M.B.), Fundación Mutua Madrileña Automovilista (to M.M.), Association International for Cancer Research (AICR08-0188 to M.M.) and 7th Framework Programme (CHEMORES LSHG-CT-2007-037,665 to M.B). The Cell Division and Cancer and the Experimental Oncology Groups are also supported by grants from the Comunidad Autónoma de Madrid (S-BIO-0283-2006) and the MICINN (Consolider-Ingenio 2010, CSD2007-00017).

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NCT00292864

NCT00372073

NCT00390117

NCT00400296

NCT00407498

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flavopiridol

tamoxifen

UCN-01

OMIM

ataxia–telangiectasia

Li–Fraumeni syndrome

mosaic variegated aneuploidy

premature chromatid separation

Seckel syndrome

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Glossary

Unscheduled proliferation

Activation of the cell cycle machinery leading to cell proliferation in the absence or presence, respectively, of appropriate mitogenic or anti-mitogenic signalling.

Genomic instability

(GIN). A tendency of the genome to acquire mutations and chromosomal aberrations owing to dysfunctional replication or repair of the cellular genome.

Chromosomal instability

(CIN). A tendency of the genome to acquire numerical aberrations in the chromosomes when chromosome segregation during mitosis is dysfunctional. CIN is frequently seen as a form of GIN, but we consider them as separate entities for clarity.

Interphase CDKs

CDKs that contribute to several cell cycle processes during interphase. In this review, we use this term to refer to CDK2, CDK4 and CDK6. This working definition does not imply that they contribute equally to the various cell cycle events (for example, G1 progression or DNA replication) that take place during interphase.

Cell cycle checkpoint

Control mechanisms that ensure the fidelity of cell division. These checkpoints verify whether the processes at each phase of the cell cycle have been accurately completed before progression into the next phase.

DNA damage checkpoint

A signal transduction pathway induced by DNA damage that blocks cell cycle progression until DNA is properly repaired.

Spindle-assembly checkpoint

A signalling pathway that monitors the correct attachment of chromosomes to spindles. Activation of this checkpoint causes cell cycle arrest as a result of the inhibition of APC/C.

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Malumbres, M., Barbacid, M. Cell cycle, CDKs and cancer: a changing paradigm. Nat Rev Cancer 9, 153–166 (2009). https://doi.org/10.1038/nrc2602

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