Suppression of endoplasmic reticulum stress-induced caspase activation and cell death by the overexpression of BCI-xL, or Bcl-2

Yayoi Murakami, Eriko Aizu-Yokota, Yoshiko Sonoda, Shigeo Ohta, Tadashi Kasahara

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

Continuous endoplasmic reticulum (ER) stress, such as the accumulation of unfolded proteins, results in cell death and relates to the pathogenesis of some neurodegenerative diseases. Treatment of brefeldin A, an inhibitor of transport between the ER and Golgi complex, induced cell death during 24h, which accompanied activation of caspase-2, caspase-3 and caspase-9, starting at 12h and increasing time-dependently up to 28h. Caspase-2 was expressed and activated in not only mitochondria and cytosol, but also in the microsomal fraction containing ER and Golgi. Of note is that overexpression of Bcl-xL or Bcl-2 in PC12 cells markedly suppressed brefeldin A-induced activation of caspases and resulting cell death. Delivery of anti-Bcl-2 antibody into the Bcl-2-overexpressed cells again recovered apoptosis. While the brefeldin A-treatment induced the phosphorylation of both c-Jun N-terminal kinase (JNK) and p38 MAPK, overexpression of Bcl-xL or Bcl-2 reduced the prolonged phosphorylation of JNK, but not of p38 MAPK. Pretreatment with a JNK inhibitor, SP600125, suppressed the brefeldin A-induced caspase-2 activation and cell death significantly. Thus, our results suggest that protective effects of Bcl-xL and Bcl-2 against brefeldin A-induced cell death appear to be dependent on the regulation of JNK activation.

Original languageEnglish
Pages (from-to)401-410
Number of pages10
JournalJournal of biochemistry
Volume141
Issue number3
DOIs
Publication statusPublished - 2007 Mar 1

Keywords

  • Bcl-2
  • Caspase-2
  • Cell death
  • Endoplasmic reticulum stress
  • JNK

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology

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