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  • Review Article
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CDC25 phosphatases in cancer cells: key players? Good targets?

Nature Reviews Cancer volume 7, pages 495–507 (2007)Cite this article

Key Points

  • Cell division cycle 25 (CDC25) phosphatases are key regulators of the eukaryotic cell cycle. They are required to control cyclin-dependent kinase (CDK) dephosphorylation and activation in a strict spatio-temporal manner.

  • CDC25A, B and C expression and activity is tightly regulated by many mechanisms, including alternative exon splicing, phosphorylation–dephosphorylation cycles, interactions with partners such as 14-3-3 proteins, intracellular localization and cell-cycle controlled degradation.

  • CDC25 phosphatases are key targets of the checkpoint machinery activated in response to DNA damage. They are functionally inactivated or degraded to stop cell-cycle progression. CDC25B activity is required for checkpoint recovery.

  • CDC25A and CDC25B overexpression are frequently found in many cancers, and are often associated with high-grade tumours and poor prognosis.

  • The contribution of CDC25 phosphatases to tumorigenesis might be related to the genetic instability associated with the checkpoint-abrogating effect of their overexpression.

  • Compounds that inhibit CDC25 phosphatase activities are currently being developed. The most potent quinonoid-based compounds identified so far are active on xenografted tumour models.

Abstract

Cell division cycle 25 (CDC25) phosphatases regulate key transitions between cell cycle phases during normal cell division, and in the event of DNA damage they are key targets of the checkpoint machinery that ensures genetic stability. Taking only this into consideration, it is not surprising that CDC25 overexpression has been reported in a significant number of human cancers. However, in light of the significant body of evidence detailing the stringent complexity with which CDC25 activities are regulated, the significance of CDC25 overexpression in a subset of cancers and its association with poor prognosis are proving difficult to assess. We will focus on the roles of CDC25 phosphatases in both normal and abnormal cell proliferation, provide a critical assessment of the current data on CDC25 overexpression in cancer, and discuss both current and future therapeutic strategies for targeting CDC25 activity in cancer treatment.

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Figure 1: The CDC25 family from an evolutionary perspective.
Figure 2: CDC25 phosphatases control key cell cycle transitions.
Figure 3: Multiple key phosphorylation events regulate CDC25 phosphatases.
Figure 4: The checkpoint hurdle to enter mitosis.
Figure 5: Overexpression of CDC25 protein in human cancers.

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Acknowledgements

We gratefully acknowledge J. Hyams (Massey University, NZ) and J. Lazo (Pittsburgh University, USA) for critical reading of this review. We thank G. Prevost and the IPSEN group for communication on the IRC083864 compound before publication. Work in our laboratory is supported by the CNRS (Centre National de la Recherche Sicientifique), the University of Toulouse and la Ligue Nationale Contre le Cancer (Equipe Labelisée 2005). R.B. is the recipient of a C.J. Martin Fellowship (National Health and Medical Research Council; Australia) and V.L. is a post-doctoral fellow with la Ligue Nationale Contre le Cancer.

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  1. LBCMCP-CNRS UMR5088, IFR109 Institut d'Exploration Fonctionnelle des Génomes, University of Toulouse, 118 route de Narbonne, Toulouse, 31062, France

    Rose Boutros, Valérie Lobjois & Bernard Ducommun

  2. UA4124. CHU Purpan, Pavillon Lefebvre TSA 40031, Toulouse, 31059, Cedex, France

    Bernard Ducommun

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  1. Rose Boutros
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Glossary

Dual-specificity protein phosphatase

A phosphoprotein phosphatase that is able to hydrolyse the phosphate ester bond on both a tyrosine and a threonine or serine residue on the same protein.

Cyclin-dependent kinase

In association with their cyclin regulatory subunits, CDKs control progression through key cell cycle transitions.

Checkpoint

Checkpoint mechanisms control the order and timing of crucial cell-cycle transitions and ensure that crucial requirements (DNA integrity, chromosome partitioning) are met, for the maintenance of the genome.

Radioresistance

A property of cells that are intrinsically resistant to usual doses of ionizing radiation.

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Boutros, R., Lobjois, V. & Ducommun, B. CDC25 phosphatases in cancer cells: key players? Good targets?. Nat Rev Cancer 7, 495–507 (2007). https://doi.org/10.1038/nrc2169

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