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.
Qin
Kefeng
K
Departments of Pathology and Microbiology-Immunology and Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
Zhao
Lili
L
Ash
Richard D
RD
McDonough
William F
WF
Zhao
Richard Y
RY
D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism*; D003300:Copper / Q000378:metabolism / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D018621:PrPC Proteins / Q000096:biosynthesis*; D011401:Promoter Regions, Genetic / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D016329:Sp1 Transcription Factor / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects* / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D018621:PrPC Proteins; D016329:Sp1 Transcription Factor; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D003300:Copper; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases