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Cdc25A phosphatase: combinatorial phosphorylation, ubiquitylation and proteolysis

Oncogene volume 23, pages 2050–2056 (2004)Cite this article

Abstract

In eukaryotic cells, control mechanisms of cell-cycle progression have evolved to accurately monitor the integrity of genetic information to be transferred to the progeny. Cdc25A phosphatase is an essential activator of cell-cycle progression and is targeted by checkpoint signals. Ubiquitylation regulates Cdc25A activity through fine tuning of its protein levels. Two different ubiquitin ligases (APC/C and SCF complex) are involved in Cdc25A turnover. While APC/C is involved in regulating Cdc25A at the exit of mitosis, SCF regulates the abundance of Cdc25A in S phase and G2. In response to DNA damage or to stalled replication, the activation of the ATM and ATR protein kinases leads to Chk1 and Chk2 activation and to Cdc25A hyperphosphorylation. These events stimulate SCF-mediated ubiquitylation of Cdc25A and its proteolysis. This contributes to delaying cell-cycle progression, thereby preventing genomic instability. Based on recent findings, we discuss the role of Cdc25A ubiquitylation and degradation in cell-cycle progression and in response to DNA damage. Moreover, we discuss the role of phosphorylation at multiple sites in triggering ubiquitylation signals.

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Acknowledgements

We thank CL Attwooll and AP Bracken for critically reading the manuscript. Work in the authors' laboratory is supported by grants from AIRC, FIRC and Telethon.

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  1. Luca Busino and Massimo Chiesa: Both these authors contributed equally to this work

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  1. European Institute of Oncology, 435 Via Ripamonti, Milan, 20141, Italy

    Luca Busino, Massimo Chiesa, Giulio F Draetta & Maddalena Donzelli

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  1. Luca Busino
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Correspondence to Maddalena Donzelli.

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Busino, L., Chiesa, M., Draetta, G. et al. Cdc25A phosphatase: combinatorial phosphorylation, ubiquitylation and proteolysis. Oncogene 23, 2050–2056 (2004). https://doi.org/10.1038/sj.onc.1207394

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