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

Kefeng Qin, Lili Zhao, Richard D. Ash, William F. McDonough, Richard Y. Zhao

Research output: Contribution to journalArticlepeer-review

26 Citations (Scopus)

Abstract

Increasing evidence suggests that the cellular prion protein (PrPC) 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 PrPC. 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 PrPC expression. Elevated PrPC correlates with reduction of intracellular copper concentration and suppression of Cu(II)-induced accumulation of reactive oxygen species and cell death. Depletion of PrPC, ATM, p53, and/or Sp1 further demonstrates that ATM is a key regulatory protein to promote activation of p53 and Sp1 leading to PrPC elevation, which is required to reduce Cu(II) toxic effects and may play an important role in modulation of intracellular copper concentration.

Original languageEnglish
Pages (from-to)4582-4593
Number of pages12
JournalJournal of Biological Chemistry
Volume284
Issue number7
DOIs
Publication statusPublished - 2009 Feb 13
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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