Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 1 de 1
Filter
Add more filters










Database
Language
Publication year range
1.
Cell Signal ; 26(12): 2903-11, 2014 Dec.
Article in English | MEDLINE | ID: mdl-25220407

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-ß. 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-ß-mediated suppression of ANT2 through NF1/Smad4 complexes contributes to oxidative stress and DNA damage during induction of cellular senescence.


Subject(s)
Adenine Nucleotide Translocator 2/metabolism , Cellular Senescence , NFI Transcription Factors/metabolism , Oxidative Stress , Smad4 Protein/metabolism , Transforming Growth Factor beta/metabolism , Adenine Nucleotide Translocator 2/genetics , Cell Line , Cell Nucleus/drug effects , Cell Nucleus/metabolism , Cellular Senescence/drug effects , Cytoprotection/drug effects , DNA Damage , Down-Regulation/drug effects , Etoposide/pharmacology , Humans , Mutation , Oxidative Stress/drug effects , Promoter Regions, Genetic , Repressor Proteins/metabolism
SELECTION OF CITATIONS
SEARCH DETAIL
...