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Nucleic Acids Research Advance Access published online on September 22, 2009
Nucleic Acids Research, doi:10.1093/nar/gkp777
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© The Author(s) 2009. Published by Oxford University Press.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.5/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Gene Regulation, Chromatin and Epigenetics

The transcriptional co-activator PCAF regulates cdk2 activity

Francesca Mateo1,2, Miriam Vidal-Laliena1,2, Núria Canela1,2, Annalisa Zecchin3, Marian Martínez-Balbás5,6, Neus Agell1,2, Mauro Giacca3,4, María Jesús Pujol1,2 and Oriol Bachs1,2,*

1Department of Cell Biology, Immunology and Neurosciences, Faculty of Medicine, University of Barcelona, 2Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain, 3Molecular Medicine Laboratory, International Centre for Engineering and Biotechnology (ICGEB), 4Department of Biomedicine, Faculty of Medicine, University of Trieste, Italy, 5Instituto de Biología Molecular de Barcelona, Consejo Superior de Investigaciones Científicas (CSIC) and 6Parc Científic de Barcelona, Barcelona, Spain

*To whom correspondence should be addressed. Tel: +34 93 403 52 86, Fax: +34 93 402 19 07; Email: obachs{at}ub.edu

Received March 31, 2009. Revised September 3, 2009. Accepted September 3, 2009.

Cyclin dependent kinases (cdks) regulate cell cycle progression and transcription. We report here that the transcriptional co-activator PCAF directly interacts with cdk2. This interaction is mainly produced during S and G2/M phases of the cell cycle. As a consequence of this association, PCAF inhibits the activity of cyclin/cdk2 complexes. This effect is specific for cdk2 because PCAF does not inhibit either cyclin D3/cdk6 or cyclin B/cdk1 activities. The inhibition is neither competitive with ATP, nor with the substrate histone H1 suggesting that somehow PCAF disturbs cyclin/cdk2 complexes. We also demonstrate that overexpression of PCAF in the cells inhibits cdk2 activity and arrests cell cycle progression at S and G2/M. This blockade is dependent on cdk2 because it is rescued by the simultaneous overexpression of this kinase. Moreover, we also observed that PCAF acetylates cdk2 at lysine 33. As this lysine is essential for the interaction with ATP, acetylation of this residue inhibits cdk2 activity. Thus, we report here that PCAF inhibits cyclin/cdk2 activity by two different mechanisms: (i) by somehow affecting cyclin/cdk2 interaction and (ii) by acetylating K33 at the catalytic pocket of cdk2. These findings identify a previously unknown mechanism that regulates cdk2 activity.


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