TGF-β/NF1/Smad4-mediated suppression of ANT2 contributes to oxidative stress in cellular senescence

0435869 - ÚMG 2015 RIV GB eng J - Journal Article
Kretová, M. - Šabová, L. - Hodný, Zdeněk - Bártek, Jiří - Kollárovič, G. - Nelson, B. D. - Hubáčková, Soňa - Luciaková, K.
TGF-β/NF1/Smad4-mediated suppression of ANT2 contributes to oxidative stress in cellular senescence.
Cellular Signalling. Roč. 26, č. 12 (2014), s. 2903-2911. ISSN 0898-6568. E-ISSN 1873-3913
R&D Projects: GA ČR GA13-17658S; GA ČR GA13-17555S
Grant - others:Slovak Grant Agency(SK) VEGA [2/0107/11]
Institutional support: RVO:68378050
Keywords : Smad * Nuclear factor 1 * Senescence * Adenine nucleotide translocase-2 * Transforming growth factor-β * Oxidative stress
Subject RIV: EB - Genetics ; Molecular Biology
Impact factor: 4.315, year: 2014

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.
Permanent Link: http://hdl.handle.net/11104/0245522