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© The Rockefeller University Press, 0021-9525/2003/8/587 $5.00
The Journal of Cell Biology, Volume 162, Number 4, 587-597

Gene expression during ER stress–induced apoptosis in neurons

Claus Reimertz^1,2, Donat Kögel^1,2, Abdelhaq Rami³, Thomas Chittenden⁴ and Jochen H.M. Prehn^1,2

¹ Interdisciplinary Center for Clinical Research, University Münster Clinics, D-48149 Münster, Germany
² Experimental Neurosurgery, Center for Neurology and Neurosurgery
³ Department of Anatomy III, Johann Wolfgang Goethe University Clinics, D-60590 Frankfurt, Germany
⁴ ImmunoGen, Inc., Cambridge, MA 02139

Address correspondence to Jochen H.M. Prehn, Experimental Neurosurgery, Center for Biological Chemistry (ZBC), HS 25 B, 4. OG, Johann Wolfgang Goethe-University Clinics, Theodor-Stern-Kai 7, D-60590 Frankfurt, Germany. Tel.: 49-69-6301-6930. Fax: 49-69-6301-5575. email: prehn{at}em.uni-frankfurt.de

Endoplasmic reticulum (ER) stress has been implicated in the pathogenesis of ischemic and neurodegenerative disorders. Treatment of human SH-SY5Y neuroblastoma cells with tunicamycin, an inhibitor of protein glycosylation, rapidly induced the expression of target genes of the unfolded protein response. However, prolonged treatment also triggered a delayed, caspase-dependent cell death. Microarray analysis of gene expression changes during tunicamycin-induced apoptosis revealed that the Bcl-2 homology domain 3-only family member, Bcl-2 binding component 3/p53 upregulated modulator of apoptosis (Bbc3/PUMA), was the most strongly induced pro-apoptotic gene. Expression of Bbc3/PUMA correlated with a Bcl-xL–sensitive release of cytochrome c and the activation of caspase-9 and -3. Increased expression of Bbc3/PUMA was also observed in p53-deficient human cells, in response to the ER stressor thapsigargin, and in rat hippocampal neurons after transient forebrain ischemia. Overexpression of Bbc3/PUMA was sufficient to trigger apoptosis in SH-SY5Y neuroblastoma cells, and human cells deficient in Bbc3/PUMA showed dramatically reduced apoptosis in response to ER stress. Our data suggest that the transcriptional induction of Bbc3/PUMA may be sufficient and necessary for ER stress–induced apoptosis.

Key Words: BH3-only proteins; transcriptome analysis; unfolded protein response; ischemia; mitochondrial apoptosis pathway

Abbreviations used in this paper: Bbc3/PUMA, Bcl-2 binding component 3/p53 upregulated modulator of apoptosis; BiP, immunoglobulin heavy chain–binding protein; CHOP, C/EBP-homologous protein; Egr-1, early growth response 1; HA, hemagglutinin; STS, staurosporine; UPR, unfolded protein response.

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