ER stress-induced apoptosis and caspase-12 activation occurs downstream of mitochondrial apoptosis involving Apaf-1

Hiroshi Shiraishi, Hideaki Okamoto, Akihiko Yoshimura, Hiroki Yoshida

Research output: Contribution to journalArticle

112 Citations (Scopus)

Abstract

Accumulation of unfolded proteins induces endoplasmic reticulum (ER) stress. Excessive and prolonged stresses lead cells to apoptosis. However, the precise molecular mechanisms of ER stress-induced apoptosis have not been fully elucidated. We investigated the involvement of the apoptosome in ER stress-induced cell death pathway using mouse embryonic fibroblasts (MEFs) and mice deficient for Apaf-1. Apaf-1-deficient MEFs showed ore resistance to ER stress-inducing reagents as compared with wild type cells. Despite comparable induction of ER stress in both wild type and Apaf-1-deficient cells, activation of caspase-3 was only observed in wild type, but not Apaf-1-deficient, MEFs. Under ER stress conditions, BAX translocated to mitochondria and cytochrome c was released from mitochondria. We also demonstrated that caspase-12 was processed downstream of Apaf-1 and caspase-3, and neither overexpression nor knockdown of caspase-12 affected susceptibility of the cells to ER stress-induced cell death. Furthermore, in the kidneys of Apaf-1-deficient mice, apoptosis induced by in vivo administration of tunicamycin was remarkably suppressed as compared with wild type mice. These data collectively demonstrated that Apaf-1 and the mitochondrial pathway of apoptosis play significant roles in ER stress-induced apoptosis.

Original languageEnglish
Pages (from-to)3958-3966
Number of pages9
JournalJournal of Cell Science
Volume119
Issue number19
DOIs
Publication statusPublished - 2006 Oct 1
Externally publishedYes

Fingerprint

Caspase 12
Endoplasmic Reticulum Stress
Apoptosis
Fibroblasts
Caspase 3
Mitochondria
Cell Death
Apoptosomes
Tunicamycin
Protein Unfolding
Cytochromes c
Kidney

Keywords

  • Apaf-1
  • Apoptosis
  • ER stress
  • Mitochondria

ASJC Scopus subject areas

  • Cell Biology

Cite this

ER stress-induced apoptosis and caspase-12 activation occurs downstream of mitochondrial apoptosis involving Apaf-1. / Shiraishi, Hiroshi; Okamoto, Hideaki; Yoshimura, Akihiko; Yoshida, Hiroki.

In: Journal of Cell Science, Vol. 119, No. 19, 01.10.2006, p. 3958-3966.

Research output: Contribution to journalArticle

Shiraishi, Hiroshi ; Okamoto, Hideaki ; Yoshimura, Akihiko ; Yoshida, Hiroki. / ER stress-induced apoptosis and caspase-12 activation occurs downstream of mitochondrial apoptosis involving Apaf-1. In: Journal of Cell Science. 2006 ; Vol. 119, No. 19. pp. 3958-3966.
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