Abstract
p53 plays a central role in neuronal cell death resulting from acute injury or disease. To define the pathway by which p53 triggers apoptosis, we used microarray analysis to identify p53 target genes specifically upregulated during apoptosis but not cell cycle arrest. This analysis identified a small subset of targets highly selective for the p53 apoptotic response, including Siva, a proapoptotic protein whose function is not well understood. Siva's expression pattern suggests that it plays an instructive role in apoptosis, and accordingly, we demonstrate that Siva is essential for p53-dependent apoptosis in cerebellar granule neurons. In addition, we determine that endogenous Siva is associated with the plasma membrane and that Caspase-8 and Bid are important for neuronal apoptosis. Our studies highlight the participation of membrane signaling events in p53's apoptotic program in primary neurons and have significant implications for understanding the mechanisms underlying pathogenesis after neuronal injury and in neurodegenerative diseases.
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Accession codes
Abbreviations
- MEFs:
-
mouse embryonic fibroblasts
- E1A-MEFs:
-
E1A-expressing MEFs
- dChip:
-
DNA-Chip analyzer
- Perp:
-
p53 effector of apoptosis related to Pmp22
- Nm23-M4:
-
expressed in non-metastatic cells 4
- Daf-1:
-
decay accelerating factor-1
- Gtse:
-
G two S phase expressed protein 1
- Apaf-1:
-
apoptotic protease activating factor-1
- CGN:
-
cerebellar granule neurons
- DIV:
-
days in vitro
- shRNAs:
-
short hairpin RNAs
- EGFR:
-
epidermal growth factor receptor
- TNF:
-
tumor necrosis factor
- S.E.M.:
-
standard error of the mean
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Acknowledgements
We are grateful to Anne Brunet, Julien Sage, Tom Johnson, Rebecca Ihrie, Steven Artandi, and Amato Giaccia for helpful comments and critical reading of the paper. We thank Jim Brown for assistance with dChip analysis, Roger Vogelmann for assistance with the iodixanol gradients, and Anne Brunet for help with neuronal preparations and lentiviral infections. The Bax−/− Bak−/− MEFs and Bid−/− mice were kindly provided by Craig Thompson and Stanley Korsmeyer, respectively. The EGFR, Na+K+ ATPase, Bid, and Caspase-8 antibodies were provided by Suzanne Pfeffer, W James Nelson, David Huang, and Matthew Bogyo, respectively. This work was supported by the NCI (PHS Grant Number CA09302-27) and Giannini Family Foundation to SBRJ, the Susan G Komen Foundation to SB, a Howard Hughes Medical Institute pre-doctoral fellowship to JIM, and the Damon Runyon Cancer Research Foundation and the Donald E and Delia B Baxter Foundation to LDA.
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Jacobs, S., Basak, S., Murray, J. et al. Siva is an apoptosis-selective p53 target gene important for neuronal cell death. Cell Death Differ 14, 1374–1385 (2007). https://doi.org/10.1038/sj.cdd.4402128
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DOI: https://doi.org/10.1038/sj.cdd.4402128
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