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PMID:10777477

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Citation

Juan, LJ, Shia, WJ, Chen, MH, Yang, WM, Seto, E, Lin, YS and Wu, CW (2000) Histone deacetylases specifically down-regulate p53-dependent gene activation. J. Biol. Chem. 275:20436-43

Abstract

p53, the most commonly mutated gene in cancer cells, directs cell cycle arrest or induces programmed cell death (apoptosis) in response to stress. It has been demonstrated that p53 activity is up-regulated in part by posttranslational acetylation. In agreement with these observations, here we show that mammalian histone deacetylase (HDAC)-1, -2, and -3 are all capable of down-regulating p53 function. Down-regulation of p53 activity by HDACs is HDAC dosage-dependent, requires the deacetylase activity of HDACs, and depends on the region of p53 that is acetylated by p300/CREB-binding protein (CBP). These results suggest that interactions of p53 and HDACs likely result in p53 deacetylation, thereby reducing its transcriptional activity. In support of this idea, GST pull-down and immunoprecipitation assays show that p53 interacts with HDAC1 both in vitro and in vivo. Furthermore, a pre-acetylated p53 peptide was significantly deacetylated by immunoprecipitated wild type HDAC1 but not deacetylase mutant. Also, co-expression of HDAC1 greatly reduced the in vivo acetylation level of p53. Finally, we report that the activation potential of p53 on the BAX promoter, a natural p53-responsive system, is reduced in the presence of HDACs. Taken together, our findings indicate that deacetylation of p53 by histone deacetylases is likely to be part of the mechanisms that control the physiological activity of p53.

Links

PubMed Online version:10.1074/jbc.M000202200

Keywords

Acetylation; Amino Acid Sequence; Down-Regulation; Gene Expression Regulation, Neoplastic/genetics; Histone Deacetylase 1; Histone Deacetylases/genetics; Histone Deacetylases/metabolism; Humans; Molecular Sequence Data; Mutation; Peptide Fragments/metabolism; Promoter Regions, Genetic; Proto-Oncogene Proteins/genetics; Proto-Oncogene Proteins c-bcl-2; Transcriptional Activation; Tumor Cells, Cultured; Tumor Suppressor Protein p53/genetics; Tumor Suppressor Protein p53/metabolism; bcl-2-Associated X Protein

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:HDAC3

enables

GO:0004407: histone deacetylase activity

ECO:0000304: author statement supported by traceable reference used in manual assertion

F

Seeded From UniProt

complete

HUMAN:HDAC3

involved_in

GO:0043066: negative regulation of apoptotic process

ECO:0000304: author statement supported by traceable reference used in manual assertion

P

Seeded From UniProt

complete

HUMAN:HDAC1

acts_upstream_of

GO:0043066: negative regulation of apoptotic process

ECO:0000304: author statement supported by traceable reference used in manual assertion

P

Seeded From UniProt

complete


See also

References

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