TGF-β/NF1/Smad4-mediated suppression of ANT2 contributes to oxidative stress in cellular senescence
| Autor: | L'udmila Šabová, Katarina Luciakova, Gabriel Kollarovic, B D Nelson, Jiri Bartek, Zdenek Hodny, Miroslava Kretova, Sona Hubackova |
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| Rok vydání: | 2014 |
| Předmět: |
Senescence
DNA damage Repressor Down-Regulation SMAD medicine.disease_cause Cell Line Adenine nucleotide Transforming Growth Factor beta medicine Humans Promoter Regions Genetic Glyceraldehyde 3-phosphate dehydrogenase Cellular Senescence Etoposide Smad4 Protein Cell Nucleus biology Adenine Nucleotide Translocator 2 Cell Biology Molecular biology Cell biology Repressor Proteins NFI Transcription Factors Oxidative Stress Cytoprotection Mutation biology.protein Carcinogenesis Oxidative stress DNA Damage |
| Zdroj: | Cellular signalling. 26(12) |
| ISSN: | 1873-3913 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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