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

• Published in: Cellular signalling 2014-12, Vol.26 (12), p.2903-2911
• Main Authors: Kretova, Miroslava, Sabova, Ludmila, Hodny, Zdenek, Bartek, Jiri, Kollarovic, Gabriel, Nelson, Buck D., Hubackova, Sona, Luciakova, Katarina
• Format: Article
• Language: English
• Subjects: Activation; Adenine nucleotide translocase-2; Adenine Nucleotide Translocator 2 - genetics; Adenine Nucleotide Translocator 2 - metabolism; Cell Line; Cell Nucleus - drug effects; Cell Nucleus - metabolism; Cellular; Cellular Senescence - drug effects; Cytoprotection - drug effects; Damage; Deoxyribonucleic acid; DNA Damage; Down-Regulation - drug effects; Etoposide - pharmacology; Fibroblasts; Formations; Humans; Mutation; NFI Transcription Factors - metabolism; Nuclear factor 1; Nucleotides; Oxidative stress; Oxidative Stress - drug effects; Promoter Regions, Genetic; Repressor Proteins - metabolism; Senescence; Smad; Smad4 Protein - metabolism; Stresses; Transforming Growth Factor beta - metabolism; Transforming growth factor-beta; Transforming growth factor-β
• ISSN: 0898-6568; 1873-3913; 1873-3913
• DOI: 10.1016/j.cellsig.2014.08.029

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. •ANT2 is repressed in all major forms of cellular senescence.•TGF-β induces formation of unique nuclear NF1/Smad4 complex that represses ANT2 gene.•ANT2 regulates the level of ROS and activation of DNA damage response.•NF1 and Smad proteins play a novel role in the regulation of senescence.