2009. Vol. 51, N 8, p. 697-705
EFFECT OF HYSTONE DEACETYLASES INHIBITOR SODIUM BUTYRATE (NaB) ON TRANSFORMANTS E1A + cHa-Ras EXPRESSING WILD TYPE p53 WITH SUPRESSED TRANSACTIVATION FUNCTION

E. I. Bukreeva, N. D. Aksenov, A. A. Bardin, V. A. Pospelov, T. V. Pospelova

Institute of Cytology RAS, St. Petersburg;
e-mail: cheverd@gmail.com

Induction of cellular senescence by various antitumour agents is a promising strategy of cancer treatment. We assessed the ability of sodium butyrate (NaB), a histone deacetylase inhibitor (HDACi), to reactivate the cellular senescence program in either E1A + cHa-Ras-transformed rat embryo fibroblasts with wild-type p53 (ERasWT) and in the isogenic cell line where p53 was inactivated due to expression of the potent genetic suppressor element GSE56 (ERasGSE56). NaB treatment increased p53 transcriptional activity and induced an irreversible G1/S cell cycle arrest in ERasWT, but not in ERasGSE56 cells. By the transient transfections method using reporter luciferase (p53-LUC) constructions, it was shown that p53-LUC activity as a marker of p53 transactivation function did not increase after X-rays exposure of transformants ERasGSE56. p53 activity in transformants ERasWT increased both after irradiation or upon NaB treatment. Interestingly, the expression of senescence-associated β-galactosidase (SA-β-Gal), widely used as a marker of senescence, as well as loss of clonogenic ability, were observed in both cell lines following NaB treatment. Thus, our results suggest that induction of p53 transcription activity could be the key determinant of HDACi-induced cell cycle arrest and senescence in transformed cells and provide an additional evidence of SA-β-Gal invalidity as a sufficient senescence marker.

Key words:  oncogenes, E1A and cHa-ras, transformation, p53 transcriptional factor, cell senescence, histone deacetylase inhibitor, sodium butyrate


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