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Degradation of cyclin A is regulated by acetylation

Oncogene volume 28, pages 2654–2666 (2009)Cite this article

Abstract

Cyclin A accumulates at the onset of S phase, remains high during G2 and early mitosis and is degraded at prometaphase. Here, we report that the acetyltransferase P/CAF directly interacts with cyclin A that as a consequence becomes acetylated at lysines 54, 68, 95 and 112. Maximal acetylation occurs simultaneously to ubiquitylation at mitosis, indicating importance of acetylation on cyclin A stability. This was further confirmed by the observation that the pseudoacetylated cyclin A mutant can be ubiquitylated whereas the nonacetylatable mutant cannot. The nonacetylatable mutant is more stable than cyclin A WT (cycA WT) and arrests cell cycle at mitosis. Moreover, in cells treated with histone deacetylase inhibitors cyclin A acetylation increases and its stability decreases, thus supporting the function of acetylation on cyclin A degradation. Although the nonacetylatable mutant cannot be ubiquitylated, it interacts with the proteins needed for its degradation (cdks, Cks, Cdc20, Cdh1 and APC/C). In fact, its association with cdks is increased and its complexes with these kinases display higher activity than control cycA WT–cdk complexes. All these results indicate that cyclin A acetylation at specific lysines is crucial for cyclin A stability and also has a function in the regulation of cycA-cdk activity.

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Acknowledgements

This research was supported by grants SAF2006-05212 and SAF2007-60491 from the Ministerio de Educación y Ciencia of Spain and RETICS RD06/0020/0010 from the Instituto de Salud Carlos III. It was also supported by grants from the National Institutes of Health (R01-GM57587, R37-CA76584, and R21-CA125173) and the Multiple Myeloma Research foundation to Michele Pagano. Michele Pagano is an Investigator with the Howard Hughes Medical Institute.

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Authors and Affiliations

  1. Department of Cell Biology and Pathology, Faculty of Medicine, University of Barcelona, Barcelona, Spain

    F Mateo, M Vidal-Laliena, N Canela, N Agell & O Bachs

  2. Department of Pathology, NYU Cancer Institute, Smilow Research Center, New York University School of Medicine, New York, NY, USA

    L Busino & M Pagano

  3. Instituto de Biología Molecular de Barcelona, Consejo Superior de Investigaciones Científicas, Barcelona, Spain

    M A Martinez-Balbas

  4. Howard Hughes Medical Institute, New York University School of Medicine, New York, NY, USA

    M Pagano

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  1. F Mateo
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Correspondence to O Bachs.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Mateo, F., Vidal-Laliena, M., Canela, N. et al. Degradation of cyclin A is regulated by acetylation. Oncogene 28, 2654–2666 (2009). https://doi.org/10.1038/onc.2009.127

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