ATM-mediated transcriptional elevation of prion in response to copper-induced oxidative stress

Increasing evidence suggests that the cellular prion protein (PrP^C) plays a protective role in response to oxidative stress, but the molecular mechanism is unclear. Here, we demonstrate that murine neuro-2a and human HeLa cells rapidly respond to an increase of intracellular copper concentration by up-regulating ataxia-telangiectasia mutated (ATM)-mediated transcription of PrP^C. Copper stimulation activates ATM by phosphorylation at Ser-1981, which leads to phosphorylation of p53 at Ser-15 and the initiation of the mitogen-activated protein kinase kinase/ extracellular-related kinases/extracellular-related kinases (MEK/ERK)/ Sp1 pathway. As results, Sp1 and p53 bind to the PrP promoter, leading to increase PrP^C expression. Elevated PrP^C correlates with reduction of intracellular copper concentration and suppression of Cu(II)-induced accumulation of reactive oxygen species and cell death. Depletion of PrP^C, ATM, p53, and/or Sp1 further demonstrates that ATM is a key regulatory protein to promote activation of p53 and Sp1 leading to PrP^C elevation, which is required to reduce Cu(II) toxic effects and may play an important role in modulation of intracellular copper concentration.