The marine product cephalostatin 1 activates an endoplasmic reticulum stress-specific and apoptosome-independent apoptotic signaling pathway

Nancy López-Antón, Anita Rudy, Nicole Barth, Lienhard M. Schmitz, George Pettit, Klaus Schulze-Osthoff, Verena M. Dirsch, Angelika M. Vollmar

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Abstract

Cephalostatin 1, a bis-steroidal marine natural product, has been reported to induce apoptosis without the requirement of an active caspase-8 or mitochondrial cytochrome c release and apoptosome formation. Here we show that despite the absence of these events, caspase-9 activation is essential for cephalostatin 1-induced apoptosis. Cephalostatin 1 initiates a rapid endoplasmic reticulum stress response characterized by phosphorylation of eukaryotic initiation factor-2 α-subunit and increased expression of the chaperone immunoglobulin heavy chain-binding protein GRP78 as well as the transcription factor C/EBP homologous protein (CHOP)/GADD153. Cephalostatin 1 activates apoptosis signal-regulating kinase 1 and c-Jun N-terminal kinase (JNK). However, this pathway does not play a major role in cephalostatin 1-induced apoptosis, as assessed by stable expression of a dominant negative apoptosis signal-regulating kinase 1. Importantly, the endoplasmic reticulum-associated caspase-4 is required and as shown by biochemical and genetic inhibition experiments, acts upstream of caspase-9 in cephalostatin-induced apoptosis.

Original languageEnglish (US)
Pages (from-to)33078-33086
Number of pages9
JournalJournal of Biological Chemistry
Volume281
Issue number44
DOIs
StatePublished - Nov 3 2006

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Apoptosomes
Endoplasmic Reticulum Stress
MAP Kinase Kinase Kinase 5
Apoptosis
Caspase 9
Transcription Factor CHOP
Eukaryotic Initiation Factor-2
Phosphorylation
Caspase 8
JNK Mitogen-Activated Protein Kinases
Caspases
Cytochromes c
Biological Products
Endoplasmic Reticulum
Molecular Biology
Transcription Factors
Chemical activation
cephalostatin I

ASJC Scopus subject areas

  • Biochemistry

Cite this

The marine product cephalostatin 1 activates an endoplasmic reticulum stress-specific and apoptosome-independent apoptotic signaling pathway. / López-Antón, Nancy; Rudy, Anita; Barth, Nicole; Schmitz, Lienhard M.; Pettit, George; Schulze-Osthoff, Klaus; Dirsch, Verena M.; Vollmar, Angelika M.

In: Journal of Biological Chemistry, Vol. 281, No. 44, 03.11.2006, p. 33078-33086.

Research output: Contribution to journalArticle

López-Antón, Nancy ; Rudy, Anita ; Barth, Nicole ; Schmitz, Lienhard M. ; Pettit, George ; Schulze-Osthoff, Klaus ; Dirsch, Verena M. ; Vollmar, Angelika M. / The marine product cephalostatin 1 activates an endoplasmic reticulum stress-specific and apoptosome-independent apoptotic signaling pathway. In: Journal of Biological Chemistry. 2006 ; Vol. 281, No. 44. pp. 33078-33086.
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AU - Pettit, George

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