ROLE OF MEK/ERK PATHWAY IN THE REGULATION OF HDACI-INDUCED SENESCENCE
OF TRANSFORMED RAT EMBRYO FIBROBLASTS
E.Yu. Kochetkova,1,2,* T.V. Bykova,1 S.G. Zubova,1 T.V. Pospelova 1
1 Institute of Cytology RAS, St. Petersburg, and 2 St. Petersburg State University;
* e-mail: lena.linnaea@gmail.com
A key regulator of cellular senescence, mTORC1 complex, is the target of many signaling cascades including
Ras/Raf/MEK/ERK-signaling cascade. In this paper we investigated the role of MEK/ERK-branch of this
cascade in the process of cellular senescence induced by histone deacetylase inhibitor (HDACI) sodium butyrate
(NaBut), in transformed rat embryo fibroblasts. Suppression of MEK / ERK activity by inhibitor PD0325901
does not prevent activation of mTORC1 complex induced by NaBut treatment. After the suppression of
MEK/ERK, activity of mTORC1 increased as well as complex mTORC2. Activation of mTOR-containing
complexes accompanied by the reorganization of the actin cytoskeleton with the formation of actin stress fibers
and the appearance of some markers of cellular senescence. In contrast to NaBut-induced senescence accumulation
of proteins was not observed, which may be due to increased activity of the degradation processes. Furthermore,
the induction of senescence in conditions suppressed MEK/ERK leads to a drastic decrease in cell viability.
Thus, NaBut-induced senescence upon suppressed activity of MEK/ERK-branch of MAP kinase cascade has
a more pronounced tumor-suppressor effect associated with stronger activation of both mTOR-complexes, reorganization
of the actin cytoskeleton and protein degradation.
Key words: HDACI — inhibitor of histone deacetylases, NaBut — sodium butyrate,
SA-β-Gal — senescence-associated β-galactosidase
| Back
| Contents
| Main |
|
