Nitric oxide induction of IRE1-α-dependent CREB phosphorylation in human glioma cells

Yeon Hyang Kim, Han Seung Joo, Doo Sik Kim

Research output: Contribution to journalArticlepeer-review

8 Scopus citations


In this study, the function of nitric oxide (NO) in endoplasmic reticulum (ER)-related cell death in human glioma cells was investigated. Treatment of human CRT-MG cells with the NO donor S-nitroso-N-acetyl-d,l-penicillamine (SNAP) and thapsigargin, an ER stress inducer, increased cytosolic Ca2+ and caused apoptosis in a dose-dependent manner. Expression of the ER-associated molecules inositol-requiring enzyme 1 (IRE1)-α, p-eIF, and Ero1-α were also elevated in thapsigargin- or NO donor-treated cells. Furthermore, thapsigargin and SNAP treatment increased IRE1-α nuclease activity, induced IRE1-α/TRAF2 complex formation, and increased p-JNK1/2 levels, suggesting that NO activates the IRE1-α/TRAF2/JNK pathway in the ER. Expression of IRE1-α increased concomitantly with cAMP responsive element binding protein (CREB) phosphorylation. siRNA knock down of IRE1-α reduced phospho-CREB levels and abolished its nuclear translocation. The levels of phospho-CREB and IRE1-α increased with NO donor concentration, which resulted in cell death. IRE1-α and phospho-CREB levels in glioblastoma U87MG cells were higher than those in normal astrocytes in response to NO. In addition, treatment with the intracellular cytokine interleukin-1β induced cell death associated with NO and increased IRE1-α and p-CREB levels. These data reveal that intracellular NO affects IRE1-α-dependent CREB phosphorylation in human glioma cells. Therefore, an IRE1-α-dependent phospho-CREB signaling pathway responsive to NO/Ca2+ may play an important role in regulating ER-related cell death in glioma.

Original languageEnglish
Pages (from-to)112-120
Number of pages9
JournalNitric Oxide - Biology and Chemistry
Issue number2
StatePublished - Sep 2010
Externally publishedYes


  • Ca
  • ER stress
  • IRE1-α
  • JNK
  • Nitric oxide
  • P-CREB


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