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TGF-beta/NF1/Smad4-mediated suppression of ANT2 contributes to oxidative stress in cellular senescence
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Antal upphovsmän: 82014 (Engelska)Ingår i: Cellular Signalling, ISSN 0898-6568, E-ISSN 1873-3913, Vol. 26, nr 12, s. 2903-2911Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

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.

Ort, förlag, år, upplaga, sidor
2014. Vol. 26, nr 12, s. 2903-2911
Nyckelord [en]
Smad, Nuclear factor 1, Senescence, Adenine nucleotide translocase-2, Transforming growth factor-beta, Oxidative stress
Nationell ämneskategori
Biologiska vetenskaper
Identifikatorer
URN: urn:nbn:se:su:diva-160570DOI: 10.1016/j.cellsig.2014.08.029ISI: 000345107700035PubMedID: 25220407OAI: oai:DiVA.org:su-160570DiVA, id: diva2:1254595
Tillgänglig från: 2018-10-09 Skapad: 2018-10-09 Senast uppdaterad: 2018-10-09Bibliografiskt granskad

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Nelson, Buck D.
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Institutionen för biokemi och biofysik
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Cellular Signalling
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