HISTONE DEACETYLASE INHIBITORS CAUSE THE TP53-DEPENDENT INDUCTION
OF ð21/Waf1 IN TUMOR CELLS CARRYING MUTATIONS IN TP53
R.A. Kovalev,1 T.A. Shtam,1 D.V. Karelov,1,2 V.S. Burdakov,1,2
A.V. Volnitskiy,1 E.M. Makarov,3 M.V. Filatov 1,2,*
1 Division of Molecular and Radiation Biophysics, SFBI Petersburg Nuclear Physics Institute (National Research Center «Kurchatov Institute»), Gatchina,
2 Department of Biophysics, St. Petersburg State Polytechnical University, and
3 Division of Biosciences, Brunel University, London, Greate Britain;
* e-mail: fil_53@mail.ru
p21/Waf1 protein is one of the main cell cycle arrest regulators and one of the most well-known transcriptional
targets of TP53 protein. Here, we demonstrated the activation of expression of the ð21/Waf1 gene when
the cells were treated to sodium butyrate (NaBu) — one of the natural inhibitors of deacetylase, and investigated
whether this phenomenon depends on the presence of functionally active TP53 protein. We compared the
effect of the NaBu treatment on the human cell line with different TP53 mutation profile, including: wild-type
TP53, single nucleotide substitutions, and the complete absence of TP53 gene. NaBu activated the TP53 protein
via hyper acetylation at lysine residue K382, without significant changes in the level of protein expression.
Western blotting demonstrated that the addition of NaBu triggers a significant increase in the p21/Waf1 protein
level in both the TP53 wild-type cells and in the cells with single nucleotide substitutions in the domain responsible
for the binding of TP53 protein to DNA. At the same time, no the p21/Waf1 protein induction was observed
in the cells with complete deletion of the TP53 gene. However, NaBu was not able to induce the p21/Waf1
production when the expression of TP53 was transiently knocked down by the p53 siRNA. Overall, our results
suggest that the NaBu-dependent induction of p21/Waf1 does require the presence of TP53 protein but unexpectedly
it can occur regardless of mutational changes in the domain responsible for the TP53 binding to DNA.
One of the hypothetical explanations is that NaBu increases the level of TP53 acetylation, and the modified
protein is able to establish a new network of protein-protein interactions or trigger some conformational changes
affecting the TP53-dependent transcriptional machinery even when its DNA binding ability is impaired.
Key words:
HDAC inhibitors, sodium butyrate, ÒÐ53, p21/Waf1/Cip1, RNA interference, ÒÐ53 mutations
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