Sequential caspase-2 and caspase-8 activation upstream of mitochondria during ceramide- and etoposide-induced apoptosis

Chiou Feng Lin, Chia-Ling Chen, Wen-Tsan Chang, Ming-Shiou Jan, Li-Jin Hsu, Ren-Huang Wu, Ming-Jer Tang, Wen Chang Chang, Yee-Shin Lin

Research output: Contribution to journalArticle

108 Citations (Scopus)

Abstract

Recently, caspase-2 was shown to act upstream of mitochondria in stress-induced apoptosis. Activation of caspase-8, a key event in death receptor-mediated apoptosis, also has been demonstrated in death receptor-independent apoptosis. The regulation of these initiator caspases, which trigger the mitochondrial apoptotic pathway, is unclear. Here we report a potential regulatory role of caspase-2 on caspase-8 during ceramide-induced apoptosis. Our results demonstrate the sequential events of initiator caspase-2 and caspase-8 activation, Bid cleavage and translocation, and mitochondrial damage followed by downstream caspase-9 and -3 activation and cell apoptosis after ceramide induction in T cell lines. The expression of truncated Bid (tBid) and the reduction in mitochondrial transmembrane potential were blocked by caspase-2 or caspase-8, but not caspase-3, knockdown using an RNA interference technique. Ceramide-induced caspase-8 activation, mitochondrial damage, and apoptosis were blocked in caspase-2 short interfering RNA-expressing cells. Therefore, caspase-2 acts upstream of caspase-8 during ceramide-induced mitochondrial apoptosis. Similarly, sequential caspase-2 and caspase-8 activation upstream of mitochondria was also observed in etoposide-induced apoptosis. These data suggest sequential initiator caspase-2 and caspase-8 activation in the mitochondrial apoptotic pathway induced by ceramide or etoposide.

Original languageEnglish
Pages (from-to)40755-40761
Number of pages7
JournalJournal of Biological Chemistry
Volume279
Issue number39
DOIs
Publication statusPublished - Sep 24 2004

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Caspase 2
Mitochondria
Caspase 8
Ceramides
Etoposide
Chemical activation
Apoptosis
Initiator Caspases
Death Domain Receptors
Caspase 3
T-cells
Caspase 9
RNA Interference
Membrane Potentials
Small Interfering RNA
RNA
T-Lymphocytes
Cell Line

ASJC Scopus subject areas

  • Biochemistry

Cite this

Sequential caspase-2 and caspase-8 activation upstream of mitochondria during ceramide- and etoposide-induced apoptosis. / Lin, Chiou Feng; Chen, Chia-Ling; Chang, Wen-Tsan; Jan, Ming-Shiou; Hsu, Li-Jin; Wu, Ren-Huang; Tang, Ming-Jer; Chang, Wen Chang; Lin, Yee-Shin.

In: Journal of Biological Chemistry, Vol. 279, No. 39, 24.09.2004, p. 40755-40761.

Research output: Contribution to journalArticle

Lin, Chiou Feng ; Chen, Chia-Ling ; Chang, Wen-Tsan ; Jan, Ming-Shiou ; Hsu, Li-Jin ; Wu, Ren-Huang ; Tang, Ming-Jer ; Chang, Wen Chang ; Lin, Yee-Shin. / Sequential caspase-2 and caspase-8 activation upstream of mitochondria during ceramide- and etoposide-induced apoptosis. In: Journal of Biological Chemistry. 2004 ; Vol. 279, No. 39. pp. 40755-40761.
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