About: Eukaryotic Initiation Factor 2α - a Downstream Effector of Mammalian Target of Rapamycin - Modulates DNA Repair and Cancer Response to Treatment

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About: Eukaryotic Initiation Factor 2α - a Downstream Effector of Mammalian Target of Rapamycin - Modulates DNA Repair and Cancer Response to Treatment Goto Sponge NotDistinct Permalink

An Entity of Type : schema:ScholarlyArticle, within Data Space : covidontheweb.inria.fr associated with source document(s)

Attributes	Values
type	Academic Article research paper schema:ScholarlyArticle
isDefinedBy	Covid-on-the-Web dataset
has title	Eukaryotic Initiation Factor 2α - a Downstream Effector of Mammalian Target of Rapamycin - Modulates DNA Repair and Cancer Response to Treatment
Creator	Keshet, G Lerenthal, Y Nakar, C Paglin, S Tuval-Kochen, L
Source	PMC
abstract	In an effort to circumvent resistance to rapamycin – an mTOR inhibitor - we searched for novel rapamycin-downstream-targets that may be key players in the response of cancer cells to therapy. We found that rapamycin, at nM concentrations, increased phosphorylation of eukaryotic initiation factor (eIF) 2α in rapamycin-sensitive and estrogen-dependent MCF-7 cells, but had only a minimal effect on eIF2α phosphorylation in the rapamycin-insensitive triple-negative MDA-MB-231 cells. Addition of salubrinal – an inhibitor of eIF2α dephosphorylation – decreased expression of a surface marker associated with capacity for self renewal, increased senescence and induced clonogenic cell death, suggesting that excessive phosphorylation of eIF2α is detrimental to the cells' survival. Treating cells with salubrinal enhanced radiation-induced increase in eIF2α phosphorylation and clonogenic death and showed that irradiated cells are more sensitive to increased eIF2α phosphorylation than non-irradiated ones. Similar to salubrinal - the phosphomimetic eIF2α variant - S51D - increased sensitivity to radiation, and both abrogated radiation-induced increase in breast cancer type 1 susceptibility gene, thus implicating enhanced phosphorylation of eIF2α in modulation of DNA repair. Indeed, salubrinal inhibited non-homologous end joining as well as homologous recombination repair of double strand breaks that were induced by I-SceI in green fluorescent protein reporter plasmids. In addition to its effect on radiation, salubrinal enhanced eIF2α phosphorylation and clonogenic death in response to the histone deacetylase inhibitor – vorinostat. Finally, the catalytic competitive inhibitor of mTOR - Ku-0063794 - increased phosphorylation of eIF2α demonstrating further the involvement of mTOR activity in modulating eIF2α phosphorylation. These experiments suggest that excessive phosphorylation of eIF2α decreases survival of cancer cells; making eIF2α a worthy target for drug development, with the potential to enhance the cytotoxic effects of established anti-neoplastic therapies and circumvent resistance to rapalogues and possibly to other drugs that inhibit upstream components of the mTOR pathway.
has issue date	2013-10-25(xsd:dateTime)
bibo:doi	10.1371/journal.pone.0077260
bibo:pmid	24204783
has license	cc-by
sha1sum (hex)	bda64532f4a16e2885868385170f8bc89ab8f789
schema:url	https://doi.org/10.1371/journal.pone.0077260
resource representing a document's title	Eukaryotic Initiation Factor 2α - a Downstream Effector of Mammalian Target of Rapamycin - Modulates DNA Repair and Cancer Response to Treatment
has PubMed Central identifier	PMC3808413
has PubMed identifier	24204783
schema:publication	PLoS One
resource representing a document's body	covid:bda64532f4a16e2885868385170f8bc89ab8f789#body_text
is schema:about of	named entity 'cells' named entity 'phosphorylation' named entity 'enhanced' named entity 'phosphorylation' named entity 'vorinostat' named entity 'mTOR' named entity 'Cancer' covid:arg/bda64532f4a16e2885868385170f8bc89ab8f789 named entity 'eIF2α' named entity 'cells' named entity 'cells' named entity 'phosphorylation' named entity 'drug development' named entity 'cells' named entity 'phosphorylation' named entity 'resistance' named entity 'potential' named entity 'minimal' named entity 'sensitive' named entity 'green fluorescent protein' named entity 'Eukaryotic' named entity 'phosphorylation' named entity 'phosphomimetic' named entity 'rapamycin' named entity 'phosphorylation' named entity 'double strand breaks' named entity 'rapamycin' named entity 'senescence' named entity 'salubrinal' named entity 'mTOR inhibitor' named entity 'salubrinal' named entity 'estrogen' named entity 'cell death' named entity 'DNA repair' named entity 'mTOR' named entity 'salubrinal' named entity 'phosphorylation' named entity 'salubrinal' named entity 'phosphorylation' named entity 'salubrinal' named entity 'DMSO' named entity 'Wolcott-Rallison syndrome' named entity 'genotoxic stress' named entity 'irradiator' named entity 'enzyme' named entity 'eIF2' named entity 'PI3K-Akt' named entity 'BRCA1' named entity 'MCF-7' named entity 'NHEJ' named entity 'plasmids' named entity 'eIF2' named entity 'phosphorylation' named entity 'phosphorylation' named entity 'protein' named entity 'cancer stem cells' named entity 'cyclin D1' named entity 'phosphorylation' named entity 'tightly regulated' named entity 'phosphorylation' named entity 'phosphorylation' named entity 'MEF' named entity 'Vorinostat' named entity 'statistical analysis' named entity 'cell death' named entity 'Non-homologous end joining' named entity 'plasmids' named entity 'cancer cells' named entity 'HeLa' named entity 'salubrinal' named entity 'SFa' named entity 'salubrinal' named entity 'Germany' named entity 'salubrinal' named entity 'FITC' named entity 'GFP' named entity 'eIF2α'

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