Počet záznamů: 1  

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

  1. 1. 0435869 - UMG-J 2015 RIV GB eng J - Článek v odborném periodiku
    Kretová, M. - Šabová, L. - Hodný, Zdeněk - Bartek, 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
    Grant CEP: GA ČR GA13-17658S; GA ČR GA13-17555S
    Grant ostatní:Slovak Grant Agency(SK) VEGA [2/0107/11]
    Institucionální podpora: RVO:68378050
    Klíčová slova: Smad * Nuclear factor 1 * Senescence * Adenine nucleotide translocase-2 * Transforming growth factor-β * Oxidative stress
    Kód oboru RIV: EB - Genetika a molekulární biologie
    Impakt faktor: 4.315, rok: 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.
    Trvalý link: http://hdl.handle.net/11104/0245522