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THE JOURNAL OF BIOLOGICAL CHEMISTRY VOL. 288, NO. 29, pp. 21096 ?1104, July 19, 2013 ?2013 by The American Society for Biochemistry and Molecular Biology, Inc. Published inside the U.S.A.Histone Deacetylase 3 Regulates Cyclin A StabilityReceived for publication, February 1, 2013, and in revised kind, June 7, 2013 Published, JBC Papers in Press, June 11, 2013, DOI 10.1074/jbc.M113.Miriam Vidal-Laliena, Edurne Gallastegui, Francesca Mateo? Marian Mart ez-Balb ? Maria Jes Pujol and Oriol Bachs1 From the Division of Cell Biology, Immunology and Neurosciences, Nav1.8 Inhibitor web Institut d’Investigacions Biom iques August Pi i Sunyer (IDIBAPS), University of Barcelona, 08036 Barcelona, Spain and the Departments of �Cell Biology and olecular Biology, Barcelona Institute of Molecular Biology, Consejo Superior de Investigaciones Cient icas (CSIC), 08028 Barcelona, SpainBackground: Cyclin A can be a regulatory subunit of cyclin-dependent kinases which can be important enzymes within the regulation of cell cycle progression. Benefits: Histone deacetylase 3 (HDAC3) regulates cyclin A deacetylation. Conclusion: HDAC3 regulates cyclin A stability by modulating cyclin A acetylation. Significance: HDAC3 regulates cell cycle progression by controlling cyclin A levels. PCAF and GCN5 mTOR Modulator drug acetylate cyclin A at distinct lysine residues targeting it for degradation at mitosis. We report here that histone deacetylase three (HDAC3) directly interacts with and deacetylates cyclin A. HDAC3 interacts using a domain integrated within the first 171 aa of cyclin A, a area involved within the regulation of its stability. In cells, overexpression of HDAC3 lowered cyclin A acetylation whereas the knocking down of HDAC3 improved its acetylation. Moreover, reduction of HDAC3 levels induced a reduce of cyclin A that can be reversed by proteasome inhibitors. These outcomes indicate that HDAC3 is in a position to regulate cyclin A degradation through mitosis via proteasome. Interestingly, HDAC3 is abruptly degraded at mitosis also via proteasome hence facilitating cyclin A acetylation by PCAF/GCN5, that will target cyclin A for degradation. For the reason that cyclin A is essential for S phase progression and mitosis entry, the knock down of HDAC3 affects cell cycle progression particularly at both, S phase and G2/M transition. In summary we propose right here that HDAC3 regulates cyclin A stability by counteracting the action of the acetylases PCAF/GCN5.Cyclin A is definitely the regulatory subunit of many members from the cyclin-dependent kinase family members (cdks)two that play an important role in the course of cell cycle progression. Particularly, cyclin A associates with and activates cdk2 thus driving S phase progression. Furthermore, in addition, it binds to and activates cdk1, a kinase vital for G2/M transition (1). The function of cyclin A-cdk complexes for the duration of cell cycle should be to phosphorylate a plethora of substrates that contain a important number of transcription things as for instance Sp1, NF-Y, FOXK2, and PR (two?), transcriptional repressors as pRb and RBP1 (6), or proteins involved in epige- This function was supported by Grants SAF2009-07769 from the Ministerio deCiencia e Innovaci of Spain and Reticc RD06/0020/0010 in the Istituto de Salud Carlos III. 1 To whom correspondence ought to be addressed: Division of Cell Biology, Immunology, and Neurosciences, Institut d’Investigacions Biom iques August Pi i Sunyer (IDIBAPS), University of Barcelona, 08036 Barcelon.
