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TGF-beta/NF1/Smad4-...
TGF-beta/NF1/Smad4-mediated suppression of ANT2 contributes to oxidative stress in cellular senescence
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Kretova, Miroslava (author)
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Sabova, Ludmila (author)
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Hodny, Zdenek (author)
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Bartek, Jiri (author)
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Kollarovic, Gabriel (author)
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- Nelson, Buck D. (author)
- Stockholms universitet,Institutionen för biokemi och biofysik
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Hubackova, Sona (author)
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Luciakova, Katarina (author)
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(creator_code:org_t)
- Elsevier BV, 2014
- 2014
- English.
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In: Cellular Signalling. - : Elsevier BV. - 0898-6568 .- 1873-3913. ; 26:12, s. 2903-2911
- Related links:
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Subject headings
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- 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-beta. 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-beta-mediated suppression of ANT2 through NF1/Smad4 complexes contributes to oxidative stress and DNA damage during induction of cellular senescence.
Subject headings
- NATURVETENSKAP -- Biologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences (hsv//eng)
Keyword
- Smad
- Nuclear factor 1
- Senescence
- Adenine nucleotide translocase-2
- Transforming growth factor-beta
- Oxidative stress
Publication and Content Type
- ref (subject category)
- art (subject category)
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