ANTIAPOPTOTIC GENE bcl-2 PREVENTS CELLULAR SENESCENCE PROGRAM
REACTIVATION INDUCED BY HISTONE DEACETYLASE INHIBITOR SODIUM BUTYRATE
IN E1A AND cHa-ras TRANSFORMED RAT FIBROBLASTS
S.A. Gordeev,1,2,* T.V. Bykova,1,2 S.G. Zubova,1 N.D. Aksenov,1 T.V. Pospelova 1,2
1 Institute of Cytology RAS, St. Petersburg, and 2 St. Petersburg State University;
* e-mail: s.a.gordeev@hotmail.com
We have investigated the role of apoptosis resistance gene bcl-2 in the activation of cellular senescence
program induced by histone deacetylase inhibitor (HDACi) sodium butyrate (NaBut) in transformed rat fibroblasts.
This study was conducted in a resistant to apoptosis induction cell line of rat embryo fibroblasts transformed
by oncogenes E1A, cHa-ras and bcl-2 (ERasBcl). The parent cell line transformed with only E1A and
cHa-ras (ERas) was used as a control. It has been found that NaBut reduces proliferation rate of ERasBcl cells
significantly weaker than of ERas transformed cells, despite the fact that the G1 cell cycle arrest was observed
in both cell lines. After NaBut treatment, hypertrophy of the apoptosis resistant transformants ERasBcl also was
reduced compared to parent cell line ERas, due to less activation of mTORC1, which is known to control the
synthesis of protein and ribosome biogenesis. The degree of mTORC1 activation was assessed by its target proteins
phosphorylation: the ribosomal S6 protein and 4E-BP1 — inhibitor of translation initiation factor eIF4E.
Since cell senescence process may be associated with changes in autophagy regulation, we analyzed the dynamics
of one of the main autophagosome formation markers — protein LC3. The accumulation of lipid-bound
form LC3-II changes significantly in ERasBcl cells after NaBut treatment and has transient nature. The set of
analyzed cellular senescence markers suggests that a high level of apoptosis resistance gene bcl-2 expression
prevents the realization of tumor-suppressor senescence program induced by HDACi sodium butyrate treatment.
Key words:
senescence, sodium butyrate, autophagy, bcl-2, HDACi
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