[Effect of histone deacetylases inhibitor sodium butyrate (NaB) on transformants E1A + cHa-Ras expressing wild type p53 with supressed transactivation function].
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 (ERas(WT)) and in the isogenic cell line where p53 was inactivated due to expression of the potent genetic suppressor element GSE56 (ERas(GSE56)). NaB treatment increased p53 transcriptional activity and induced an irreversible G1/S cell cycle arrest in ERas(WT), but not in ERas(GSE56) 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 ERas(GSE56). p53 activity in transformants ERas(WT) increased both after irradiation or upon NaB treatment. Interestingly, the expression of senescence-associated beta-galactosidase (SA-beta-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-beta-Gal invalidity as a sufficient senescence marker.
Bukreeva
E I
EI
Aksenov
N D
ND
Bardin
A A
AA
Pospelov
V A
VA
Pospelova
T V
TV
D017500:Adenovirus E1A Proteins / Q000235:genetics; D000818:Animals; D002087:Butyrates / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000378:metabolism*; D016922:Cellular Senescence / Q000187:drug effects / Q000502:physiology*; D015536:Down-Regulation; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D056572:Histone Deacetylase Inhibitors; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D051381:Rats; D015533:Transcriptional Activation / Q000187:drug effects / Q000528:radiation effects; D014170:Transformation, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology*; D001616:beta-Galactosidase / Q000378:metabolism
D017500:Adenovirus E1A Proteins; D002087:Butyrates; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D016159:Tumor Suppressor Protein p53; D001616:beta-Galactosidase; D016283:Proto-Oncogene Proteins p21(ras)