As(III) transcriptionally activates the gadd45a gene via the formation of H2O2.
Arsenic is a ubiquitous environmental contaminant associated with increased risks of human cancers of the skin, lung, bladder, and prostate. Intriguingly, it is also used to treat certain types of leukemia. It has recently been suggested that these paradoxic effects may be mediated by arsenic's ability to simultaneously activate DNA damage and apoptotic and transformation pathways. Here, we investigate the effects of arsenic exposure on the induction of the growth arrest and DNA damage protein 45 alpha (GADD45 alpha), which is thought to play roles in apoptosis, DNA damage response, and cell cycle arrest. We found that arsenic transcriptionally activates the gadd45 alpha promoter located in a 153-bp region between -234 and -81, relative to the transcriptional start site. In addition, this transcriptional induction was abrogated in the presence of H2O2 scavengers, suggesting a role for H2O2 in the transcriptional control of the gadd45a gene through a Fenton-like free radical mechanism.
Bower
Jacquelyn J
JJ
Pathology and Physiology Research Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, WV 26505, USA.
Leonard
Stephen S
SS
Chen
Fei
F
Shi
Xianglin
X
D001151:Arsenic / Q000494:pharmacology*; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D004578:Electron Spin Resonance Spectroscopy; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics*; D010101:Oxygen Consumption; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics; D015533:Transcriptional Activation / Q000187:drug effects*; D000097642:GADD45 Proteins
D001151:Arsenic; D018797:Cell Cycle Proteins; D006861:Hydrogen Peroxide; D009687:Nuclear Proteins; D012333:RNA, Messenger; C439070:GADD45A protein, human; D000097642:GADD45 Proteins