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Statements

Subject Item
n2:RIV%2F00216208%3A11150%2F14%3A10218687%21RIV15-MSM-11150___
rdf:type
skos:Concept n20:Vysledek
rdfs:seeAlso
http://www.mdpi.com/1422-0067/15/7/12007
dcterms:description
DNA damaging agents such as ionizing radiation or chemotherapy are frequently used in oncology. DNA damage response (DDR)-triggered by radiation-induced double strand breaks-is orchestrated mainly by three Phosphatidylinositol 3-kinase-related kinases (PIKKs): Ataxia teleangiectasia mutated (ATM), DNA-dependent protein kinase (DNA-PK) and ATM and Rad3-related kinase (ATR). Their activation promotes cell-cycle arrest and facilitates DNA damage repair, resulting in radioresistance. Recently developed specific ATR inhibitor, VE-821 (3-amino-6-(4-(methylsulfonyl)phenyl)-N-phenylpyrazine-2-carboxamide), has been reported to have a significant radio- and chemo-sensitizing effect delimited to cancer cells (largely p53-deficient) without affecting normal cells. In this study, we employed SILAC-based quantitative phosphoproteomics to describe the mechanism of the radiosensitizing effect of VE-821 in human promyelocytic leukemic cells HL-60 (p53-negative). Hydrophilic interaction liquid chromatography (HILIC)-prefractionation with TiO2-enrichment and nano-liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis revealed 9834 phosphorylation sites. Proteins with differentially up-/down-regulated phosphorylation were mostly localized in the nucleus and were involved in cellular processes such as DDR, all phases of the cell cycle, and cell division. Moreover, sequence motif analysis revealed significant changes in the activities of kinases involved in these processes. Taken together, our data indicates that ATR kinase has multiple roles in response to DNA damage throughout the cell cycle and that its inhibitor VE-821 is a potent radiosensitizing agent for p53-negative HL-60 cells. DNA damaging agents such as ionizing radiation or chemotherapy are frequently used in oncology. DNA damage response (DDR)-triggered by radiation-induced double strand breaks-is orchestrated mainly by three Phosphatidylinositol 3-kinase-related kinases (PIKKs): Ataxia teleangiectasia mutated (ATM), DNA-dependent protein kinase (DNA-PK) and ATM and Rad3-related kinase (ATR). Their activation promotes cell-cycle arrest and facilitates DNA damage repair, resulting in radioresistance. Recently developed specific ATR inhibitor, VE-821 (3-amino-6-(4-(methylsulfonyl)phenyl)-N-phenylpyrazine-2-carboxamide), has been reported to have a significant radio- and chemo-sensitizing effect delimited to cancer cells (largely p53-deficient) without affecting normal cells. In this study, we employed SILAC-based quantitative phosphoproteomics to describe the mechanism of the radiosensitizing effect of VE-821 in human promyelocytic leukemic cells HL-60 (p53-negative). Hydrophilic interaction liquid chromatography (HILIC)-prefractionation with TiO2-enrichment and nano-liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis revealed 9834 phosphorylation sites. Proteins with differentially up-/down-regulated phosphorylation were mostly localized in the nucleus and were involved in cellular processes such as DDR, all phases of the cell cycle, and cell division. Moreover, sequence motif analysis revealed significant changes in the activities of kinases involved in these processes. Taken together, our data indicates that ATR kinase has multiple roles in response to DNA damage throughout the cell cycle and that its inhibitor VE-821 is a potent radiosensitizing agent for p53-negative HL-60 cells.
dcterms:title
Radiosensitization of Human Leukemic HL-60 Cells by ATR Kinase Inhibitor (VE-821): Phosphoproteomic Analysis Radiosensitization of Human Leukemic HL-60 Cells by ATR Kinase Inhibitor (VE-821): Phosphoproteomic Analysis
skos:prefLabel
Radiosensitization of Human Leukemic HL-60 Cells by ATR Kinase Inhibitor (VE-821): Phosphoproteomic Analysis Radiosensitization of Human Leukemic HL-60 Cells by ATR Kinase Inhibitor (VE-821): Phosphoproteomic Analysis
skos:notation
RIV/00216208:11150/14:10218687!RIV15-MSM-11150___
n3:aktivita
n14:S n14:P
n3:aktivity
P(GPP206/12/P338), S
n3:cisloPeriodika
7
n3:dodaniDat
n9:2015
n3:domaciTvurceVysledku
n18:9950354 n18:6518672
n3:druhVysledku
n11:J
n3:duvernostUdaju
n8:S
n3:entitaPredkladatele
n12:predkladatel
n3:idSjednocenehoVysledku
41230
n3:idVysledku
RIV/00216208:11150/14:10218687
n3:jazykVysledku
n16:eng
n3:klicovaSlova
HL-60 cells; leukemia; SILAC; titanium dioxide chromatography; quantitative phosphoproteomics; radio-sensitization; DNA damage response; ATR kinase; VE-821; Small-molecule kinase inhibitors
n3:klicoveSlovo
n7:leukemia n7:ATR%20kinase n7:Small-molecule%20kinase%20inhibitors n7:quantitative%20phosphoproteomics n7:titanium%20dioxide%20chromatography n7:SILAC n7:DNA%20damage%20response n7:HL-60%20cells n7:VE-821 n7:radio-sensitization
n3:kodStatuVydavatele
CH - Švýcarská konfederace
n3:kontrolniKodProRIV
[413BF9769BE1]
n3:nazevZdroje
International Journal of Molecular Sciences
n3:obor
n19:EB
n3:pocetDomacichTvurcuVysledku
2
n3:pocetTvurcuVysledku
7
n3:projekt
n13:GPP206%2F12%2FP338
n3:rokUplatneniVysledku
n9:2014
n3:svazekPeriodika
15
n3:tvurceVysledku
Vávrová, Jiřina Link, Marek Šalovská, Barbora Řezáčová, Martina Tichý, Aleš Fabrik, Ivo Ďurišová, Kamila
n3:wos
000340038500051
s:issn
1422-0067
s:numberOfPages
20
n10:doi
10.3390/ijms150712007
n17:organizacniJednotka
11150