TGF-β/NF1/Smad4-mediated suppression of ANT2 contributes to oxidative stress in cellular senescence
Miroslava Kretova1, Ludmila Sabova1, Zdenek Hodny2
1Cancer Research Institute, Slovak Academy of Sciences, Vlarska 7, 833 91 Bratislava, Slovak Republic.
Abstract:
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.
Insights
Cellular senescence involves oxidative stress and DNA damage. Researchers found that reduced adenine nucleotide translocase-2 (ANT2) expression, driven by TGF-β and NF1/Smad complexes, contributes to these processes.
Area of Science:
- Cellular Biology
- Molecular Biology
- Biochemistry
Background:
- Cellular senescence, characterized by oxidative stress and DNA damage response (DDR) activation, is crucial in aging and cancer.
- Adenine nucleotide translocase-2 (ANT2) is a key mitochondrial protein involved in cellular energy metabolism.
Purpose of the Study:
- To investigate the role of ANT2 in cellular senescence.
- To elucidate the molecular mechanisms regulating ANT2 expression during senescence.
Main Methods:
- Analysis of ANT2 expression in different forms of cellular senescence (replicative, oncogene-induced, drug-induced).
- Investigation of NF1/Smad transcription repressor complexes binding to the ANT2 gene promoter.
- Use of siRNA to knock down ANT2 expression in proliferating cells.
- Assessment of reactive oxygen species (ROS) levels and DDR activation.
Main Results:
- ANT2 is consistently down-regulated in all major forms of cellular senescence in human cells.
- NF1/Smad transcription repressor complexes bind to the ANT2 promoter, repressing its expression.
- TGF-β signaling is involved in the formation of these complexes and ANT2 repression.
- ANT2 knockdown in proliferating cells increases ROS and activates DDR, exacerbating damage and apoptosis upon etoposide treatment.
Conclusions:
- TGF-β-mediated suppression of ANT2 via NF1/Smad4 complexes contributes to oxidative stress and DNA damage during cellular senescence.
- ANT2 plays a protective role against senescence-associated oxidative stress and DNA damage.
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