The fully linked HTML version of this article has now been published.
JCS ePress
online publication date 5 Sep 2006
doi: 10.1242/jcs.03160
Research Article
ER stress-induced apoptosis and caspase-12 activation occurs downstream of mitochondrial apoptosis involving Apaf-1
Hiroshi Shiraishi,
Hideaki Okamoto,
Akihiko Yoshimura,
and
Hiroki Yoshida*
* Author for correspondence (e-mail: yoshidah{at}med.saga-u.ac.jp)
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 more 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.

CiteULike
Complore
Connotea
Del.icio.us
Digg
Reddit
Technorati
Twitter What's this?
This article has been cited by other articles:

|
 |

|
 |
 
M. F. Tonnesen, L. G. Grunnet, J. Friberg, A. K. Cardozo, N. Billestrup, D. L. Eizirik, J. Storling, and T. Mandrup-Poulsen
Inhibition of Nuclear Factor-{kappa}B or Bax Prevents Endoplasmic Reticulum Stress- But Not Nitric Oxide-Mediated Apoptosis in INS-1E Cells
Endocrinology,
September 1, 2009;
150(9):
4094 - 4103.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
G. Matsuura, N. Morinaga, K. Yahiro, R. Komine, J. Moss, H. Yoshida, and M. Noda
Novel Subtilase Cytotoxin Produced by Shiga-Toxigenic Escherichia coli Induces Apoptosis in Vero Cells via Mitochondrial Membrane Damage
Infect. Immun.,
July 1, 2009;
77(7):
2919 - 2924.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
E. Szegezdi, D. C. MacDonald, T. Ni Chonghaile, S. Gupta, and A. Samali
Bcl-2 family on guard at the ER
Am J Physiol Cell Physiol,
May 1, 2009;
296(5):
C941 - C953.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
X. Lei, S. Zhang, A. Bohrer, and S. Ramanadham
Calcium-independent Phospholipase A2 (iPLA2{beta})-mediated Ceramide Generation Plays a Key Role in the Cross-talk between the Endoplasmic Reticulum (ER) and Mitochondria during ER Stress-induced Insulin-secreting Cell Apoptosis
J. Biol. Chem.,
December 12, 2008;
283(50):
34819 - 34832.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
L.-p. Yang, L.-m. Wu, X.-j. Guo, and M. O. M. Tso
Activation of Endoplasmic Reticulum Stress in Degenerating Photoreceptors of the rd1 Mouse
Invest. Ophthalmol. Vis. Sci.,
November 1, 2007;
48(11):
5191 - 5198.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
J. Guo, T. Zhu, Z.-X. J. Xiao, and C.-Y. Chen
Modulation of Intracellular Signaling Pathways to Induce Apoptosis in Prostate Cancer Cells
J. Biol. Chem.,
August 17, 2007;
282(33):
24364 - 24372.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
A. Masud, A. Mohapatra, S. A. Lakhani, A. Ferrandino, R. Hakem, and R. A. Flavell
Endoplasmic Reticulum Stress-induced Death of Mouse Embryonic Fibroblasts Requires the Intrinsic Pathway of Apoptosis
J. Biol. Chem.,
May 11, 2007;
282(19):
14132 - 14139.
[Abstract]
[Full Text]
[PDF]
|
 |
|
© The Company of Biologists Ltd 2006