title: [Role of MEK/ERK pathway in the regulation of HDACI-induced senescence of transformed rat embryo fibroblasts].
abstract: 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.
authors.forename: E Iu
authors.initials: EIu
authors.lastname: Kochetkova
authors.forename: T V
authors.initials: TV
authors.lastname: Bykova
authors.forename: S G
authors.initials: SG
authors.lastname: Zubova
authors.forename: T V
authors.initials: TV
authors.lastname: Pospelova
mesh_terms: D008841:Actin Cytoskeleton / Q000187:drug effects / Q000648:ultrastructure; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D020148:Butyric Acid / Q000494:pharmacology; D002461:Cell Line, Transformed; D002470:Cell Survival / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects / Q000235:genetics*; D004159:Diphenylamine / Q000031:analogs & derivatives / Q000494:pharmacology; D004622:Embryo, Mammalian; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D005786:Gene Expression Regulation; D056284:Histone Deacetylase 1 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D001549:Benzamides; D056572:Histone Deacetylase Inhibitors; D046912:Multiprotein Complexes; D020148:Butyric Acid; C506614:mirdametinib; D004159:Diphenylamine; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C515890:Hdac1 protein, rat; D056284:Histone Deacetylase 1; D016283:Proto-Oncogene Proteins p21(ras)