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Statements

Subject Item
n2:RIV%2F68378050%3A_____%2F14%3A00442568%21RIV15-GA0-68378050
rdf:type
skos:Concept n14:Vysledek
dcterms:description
Oxidative stress and persistent activation of DNA damage response (DDR) are causally involved in the development of cellular senescence, a phenomenon implicated in fundamental (patho)physiological processes such as aging, fetal development and tumorigenesis. Here, we report that adenine nucleotide translocase-2 (ANT2) is consistently down-regulated in all three major forms of cellular senescence: replicative, oncogene-induced and drug-induced, in both normal and cancerous human cells. We previously reported formation of novel NF1/Smad transcription repressor complexes in growth-arrested fibroblasts. Here we show that such complexes form in senescent cells. Mechanistically, binding of the NF1/Smad complexes to the NF1-dependent repressor elements in the ANT2 gene promoter repressed ANT2 expression. Etoposide-induced formation of these complexes and repression of ANT2 were relatively late events co-incident with production and secretion of, and dependent on, TGF-β. siRNA-mediated knock-down of ANT2 in proliferating cells resulted in increased levels of reactive oxygen species (ROS) and activation of the DDR. Knock-down of ANT2, together with etoposide treatment, further intensified ROS production and DNA damage signaling, leading to enhanced apoptosis. Together, our data show that TGF-β-mediated suppression of ANT2 through NF1/Smad4 complexes contributes to oxidative stress and DNA damage during induction of cellular senescence. Oxidative stress and persistent activation of DNA damage response (DDR) are causally involved in the development of cellular senescence, a phenomenon implicated in fundamental (patho)physiological processes such as aging, fetal development and tumorigenesis. Here, we report that adenine nucleotide translocase-2 (ANT2) is consistently down-regulated in all three major forms of cellular senescence: replicative, oncogene-induced and drug-induced, in both normal and cancerous human cells. We previously reported formation of novel NF1/Smad transcription repressor complexes in growth-arrested fibroblasts. Here we show that such complexes form in senescent cells. Mechanistically, binding of the NF1/Smad complexes to the NF1-dependent repressor elements in the ANT2 gene promoter repressed ANT2 expression. Etoposide-induced formation of these complexes and repression of ANT2 were relatively late events co-incident with production and secretion of, and dependent on, TGF-β. siRNA-mediated knock-down of ANT2 in proliferating cells resulted in increased levels of reactive oxygen species (ROS) and activation of the DDR. Knock-down of ANT2, together with etoposide treatment, further intensified ROS production and DNA damage signaling, leading to enhanced apoptosis. Together, our data show that TGF-β-mediated suppression of ANT2 through NF1/Smad4 complexes contributes to oxidative stress and DNA damage during induction of cellular senescence.
dcterms:title
TGF- β /NF1/Smad4-mediated suppression of ANT2 contributes to oxidative stress in cellular senescence TGF- β /NF1/Smad4-mediated suppression of ANT2 contributes to oxidative stress in cellular senescence
skos:prefLabel
TGF- β /NF1/Smad4-mediated suppression of ANT2 contributes to oxidative stress in cellular senescence TGF- β /NF1/Smad4-mediated suppression of ANT2 contributes to oxidative stress in cellular senescence
skos:notation
RIV/68378050:_____/14:00442568!RIV15-GA0-68378050
n3:aktivita
n10:P n10:I
n3:aktivity
I, P(GA13-17555S), P(GA13-17658S)
n3:cisloPeriodika
12
n3:dodaniDat
n13:2015
n3:domaciTvurceVysledku
n6:6201822 n6:5889715 n6:6225616
n3:druhVysledku
n4:J
n3:duvernostUdaju
n18:S
n3:entitaPredkladatele
n16:predkladatel
n3:idSjednocenehoVysledku
50213
n3:idVysledku
RIV/68378050:_____/14:00442568
n3:jazykVysledku
n12:eng
n3:klicovaSlova
Smad; Nuclear factor 1; Senescence; Adenine nucleotide translocase-2; Transforming growth factor- β; Oxidative stress
n3:klicoveSlovo
n7:Nuclear%20factor%201 n7:Smad n7:Senescence n7:Transforming%20growth%20factor-%20%CE%B2 n7:Adenine%20nucleotide%20translocase-2 n7:Oxidative%20stress
n3:kodStatuVydavatele
GB - Spojené království Velké Británie a Severního Irska
n3:kontrolniKodProRIV
[C2A6DBF081BC]
n3:nazevZdroje
Cellular Signalling
n3:obor
n15:EB
n3:pocetDomacichTvurcuVysledku
3
n3:pocetTvurcuVysledku
8
n3:projekt
n5:GA13-17555S n5:GA13-17658S
n3:rokUplatneniVysledku
n13:2014
n3:svazekPeriodika
26
n3:tvurceVysledku
Luciaková, K. Bartek, Jiří Kollárovič, G. Kretová, M. Nelson, B. D. Hodný, Zdeněk Sabová, L. Hubáčková, Soňa
s:issn
0898-6568
s:numberOfPages
9
n17:doi
10.1016/j.cellsig.2014.08.029