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PNAS 97 (14): 7835-7840

Copyright © 2000 by the National Academy of Sciences.


Regulation of histone deacetylase 4 and 5 and transcriptional activity by 14-3- 3-dependent cellular localization

Christina M. Grozinger Stuart L. Schreiber*

Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, MA 02138

Contributed by Stuart L. Schreiber

Accepted for publication May 3, 2000.

Abstract: Transcription is controlled in part by the dynamic acetylation and deacetylation of histone proteins. The latter process is mediated by histone deacetylases (HDACs). Previous analysis of the regulation of HDAC activity in transcription has focused primarily on the recruitment of HDAC proteins to specific promoters or chromosomal domains by association with DNA-binding proteins. To characterize the cellular function of the recently identified HDAC4 and HDAC5 proteins, complexes were isolated by immunoprecipitation. Both HDACs were found to interact with14-3-3 proteins at three phosphorylation sites. The association of 14-3-3 with HDAC4 and HDAC5 results in the sequestration of these proteins in the cytoplasm. Loss of this interaction allows HDAC4 and HDAC5 to translocate to the nucleus, interact with HDAC3, and repress gene expression. Regulation of the cellular localization of HDAC4 and HDAC5 by 14-3-3 represents a mechanism for controlling the transcriptional activity of these class II HDAC proteins.

* To whom reprint requests should be addressed. E-mail: sls{at}

Article published online before print: Proc. Natl. Acad. Sci. USA, 10.1073/pnas.140199597.

Article and publication date are at

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Sci. STKE 2005, re10
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Cross-species Sequence Analysis Reveals Multiple Charged Residue-rich Domains That Regulate Nuclear/Cytoplasmic Partitioning and Membrane Localization of A Kinase Anchoring Protein 12 (SSeCKS/Gravin).
J. W. Streb and J. M. Miano (2005)
J. Biol. Chem. 280, 28007-28014
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Repression of Runx2 function by TGF-{beta} through recruitment of class II histone deacetylases by Smad3.
J. S. Kang, T. Alliston, R. Delston, and R. Derynck (2005)
EMBO J. 24, 2543-2555
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Calmodulin-dependent protein kinase IV regulates nuclear export of Cabin1 during T-cell activation.
F. Pan, A. R. Means, and J. O. Liu (2005)
EMBO J. 24, 2104-2113
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An expression screen reveals modulators of class II histone deacetylase phosphorylation.
S. Chang, S. Bezprozvannaya, S. Li, and E. N. Olson (2005)
PNAS 102, 8120-8125
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Promotion of importin {alpha}-mediated nuclear import by the phosphorylation-dependent binding of cargo protein to 14-3-3.
C. Faul, S. Huttelmaier, J. Oh, V. Hachet, R. H. Singer, and P. Mundel (2005)
J. Cell Biol. 169, 415-424
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Class II Histone Deacetylases: from Sequence to Function, Regulation, and Clinical Implication.
X.-J. Yang and S. Gregoire (2005)
Mol. Cell. Biol. 25, 2873-2884
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Protein Kinase D1 Phosphorylates HDAC7 and Induces Its Nuclear Export after T-cell Receptor Activation.
M. Parra, H. Kasler, T. A. McKinsey, E. N. Olson, and E. Verdin (2005)
J. Biol. Chem. 280, 13762-13770
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Isoform-specific Subcellular Localization among 14-3-3 Proteins in Arabidopsis Seems to be Driven by Client Interactions.
A.-L. Paul, P. C. Sehnke, and R. J. Ferl (2005)
Mol. Biol. Cell 16, 1735-1743
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Activity-dependent and -independent nuclear fluxes of HDAC4 mediated by different kinases in adult skeletal muscle.
Y. Liu, W. R. Randall, and M. F. Schneider (2005)
J. Cell Biol. 168, 887-897
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Phosphorylation of histone deacetylase 7 by protein kinase D mediates T cell receptor-induced Nur77 expression and apoptosis.
F. Dequiedt, J. Van Lint, E. Lecomte, V. Van Duppen, T. Seufferlein, J. R. Vandenheede, R. Wattiez, and R. Kettmann (2005)
J. Exp. Med. 201, 793-804
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Structural Determinants of Constitutive Androstane Receptor Required for Its Glucocorticoid Receptor Interacting Protein-1-mediated Nuclear Accumulation.
J. Xia and B. Kemper (2005)
J. Biol. Chem. 280, 7285-7293
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SMRT and N-CoR Corepressors Are Regulated by Distinct Kinase Signaling Pathways.
B. A. Jonas and M. L. Privalsky (2004)
J. Biol. Chem. 279, 54676-54686
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The CRM1 Nuclear Export Receptor Controls Pathological Cardiac Gene Expression.
B. C. Harrison, C. R. Roberts, D. B. Hood, M. Sweeney, J. M. Gould, E. W. Bush, and T. A. McKinsey (2004)
Mol. Cell. Biol. 24, 10636-10649
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Recruitment of I{kappa}B{alpha} to the hes1 promoter is associated with transcriptional repression.
C. Aguilera, R. Hoya-Arias, G. Haegeman, L. Espinosa, and A. Bigas (2004)
PNAS 101, 16537-16542
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Protein Kinases C and D Mediate Agonist-Dependent Cardiac Hypertrophy through Nuclear Export of Histone Deacetylase 5.
R. B. Vega, B. C. Harrison, E. Meadows, C. R. Roberts, P. J. Papst, E. N. Olson, and T. A. McKinsey (2004)
Mol. Cell. Biol. 24, 8374-8385
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