title: The endoplasmic reticulum stress response factor CHOP-10 protects against hypoxia-induced neuronal death.
abstract: Hypoxia-induced gene expression is a critical determinant of neuron survival after stroke. Understanding the cell autonomous genetic program controlling adaptive and pathological transcription could have important therapeutic implications. To identify the factors that modulate delayed neuronal apoptosis after hypoxic injury, we developed an in vitro culture model that recapitulates these divergent responses and characterized the sequence of gene expression changes using microarrays. Hypoxia induced a disproportionate number of bZIP transcription factors and related targets involved in the endoplasmic reticulum stress response. Although the temporal and spatial aspects of ATF4 expression correlated with neuron loss, our results did not support the anticipated pathological role for delayed CHOP expression. Rather, CHOP deletion enhanced neuronal susceptibility to both hypoxic and thapsigargin-mediated injury and attenuated brain-derived neurotrophic factor-induced neuroprotection. Also, enforced expression of CHOP prior to the onset of hypoxia protected wild-type cultures against subsequent injury. Collectively, these findings indicate CHOP serves a more complex role in the neuronal response to hypoxic stress with involvement in both ischemic preconditioning and delayed neuroprotection.
authors.affiliation: Department of Neurology, University of Rochester Medical Center, Rochester, New York 14642, USA. marc_halterman@urmc.rochester.edu
authors.forename: Marc W
authors.initials: MW
authors.lastname: Halterman
authors.forename: Molly
authors.initials: M
authors.lastname: Gill
authors.forename: Chris
authors.initials: C
authors.lastname: DeJesus
authors.forename: Mitsunori
authors.initials: M
authors.lastname: Ogihara
authors.forename: Nina F
authors.initials: NF
authors.lastname: Schor
authors.forename: Howard J
authors.initials: HJ
authors.lastname: Federoff
mesh_terms: D000818:Animals; D017209:Apoptosis; D016923:Cell Death; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005786:Gene Expression Regulation; D000860:Hypoxia / Q000378:metabolism; D019194:Ischemic Preconditioning; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism; D009693:Nucleic Acid Hybridization; D020411:Oligonucleotide Array Sequence Analysis; D019284:Thapsigargin / Q000494:pharmacology; D051742:Transcription Factor CHOP / Q000378:metabolism*
chemical_list: C497250:Ddit3 protein, mouse; D051742:Transcription Factor CHOP; D019284:Thapsigargin
references.citation: Mol Cell Neurosci. 2008 Jun;38(2):125-37
references.pmid: 18439838
references.citation: Neuron. 2002 Nov 14;36(4):585-96
references.pmid: 12441049
references.citation: RNA. 2006 Jun;12(6):1074-83
references.pmid: 16601206
references.citation: J Neurochem. 2004 Oct;91(1):1-8
references.pmid: 15379881
references.citation: Stroke. 2000 Sep;31(9):2212-7
references.pmid: 10978054
references.citation: Nat Protoc. 2008;3(6):1101-8
references.pmid: 18546601
references.citation: Acta Neuropathol. 1984;64(2):139-47
references.pmid: 6475501
references.citation: Neuroscience. 2008 Jan 2;151(1):111-9
references.pmid: 18082969
references.citation: Semin Neurol. 2006 Sep;26(4):422-31
references.pmid: 16969743
references.citation: Neuropathology. 2000 Sep;20 Suppl:S95-7
references.pmid: 11037198
references.citation: Ann Neurol. 2001 Jul;50(1):93-103
references.pmid: 11456315
references.citation: Science. 2003 Jun 27;300(5628):2097-101
references.pmid: 12805554
references.citation: EMBO J. 2005 Mar 23;24(6):1243-55
references.pmid: 15775988
references.citation: Nat Rev Neurosci. 2006 Jun;7(6):437-48
references.pmid: 16715053
references.citation: FEBS Lett. 2006 Jun 12;580(14):3462-8
references.pmid: 16716308
references.citation: Science. 2007 Nov 9;318(5852):944-9
references.pmid: 17991856
references.citation: Genes Dev. 1998 Apr 1;12(7):982-95
references.pmid: 9531536
references.citation: J Cereb Blood Flow Metab. 2004 Mar;24(3):343-9
references.pmid: 15091115
references.citation: Stroke. 2007 Feb;38(2 Suppl):652-60
references.pmid: 17261709
references.citation: J Neurosci Res. 2007 Jun;85(8):1674-84
references.pmid: 17455323
references.citation: Science. 1996 May 31;272(5266):1347-9
references.pmid: 8650547
references.citation: Brain Res. 2004 Oct 22;1024(1-2):89-96
references.pmid: 15451369
references.citation: J Exp Med. 2008 May 12;205(5):1227-42
references.pmid: 18458112
references.citation: J Stroke Cerebrovasc Dis. 2007 Mar-Apr;16(2):82-3
references.pmid: 17689399
references.citation: Proc Natl Acad Sci U S A. 2005 Sep 13;102(37):13212-7
references.pmid: 16141338
references.citation: PLoS One. 2007 Sep 12;2(9):e874
references.pmid: 17849004
references.citation: Genes Dev. 2004 Dec 15;18(24):3066-77
references.pmid: 15601821
references.citation: J Neurosci. 1995 Oct;15(10):6364-76
references.pmid: 7472401
references.citation: Mol Cell Biol. 2001 Feb;21(4):1249-59
references.pmid: 11158311
references.citation: Neurosci Lett. 2008 Dec 26;448(2):194-9
references.pmid: 18938215
references.citation: J Cereb Blood Flow Metab. 1993 Jul;13(4):558-67
references.pmid: 8314911
references.citation: J Cereb Blood Flow Metab. 1996 Mar;16(2):195-201
references.pmid: 8594050
references.citation: J Biol Chem. 2004 Apr 2;279(14):13792-9
references.pmid: 14742429
references.citation: Cell Death Differ. 2004 Apr;11(4):403-15
references.pmid: 14752508
references.citation: J Neurosci. 2008 Feb 27;28(9):2168-78
references.pmid: 18305250
references.citation: Neurosci Lett. 1990 Nov 27;120(1):117-9
references.pmid: 2293081
references.citation: Ann Neurol. 1994 Dec;36(6):864-70
references.pmid: 7998772
references.citation: Annu Rev Cell Dev Biol. 2002;18:575-99
references.pmid: 12142265
references.citation: J Neurochem. 2004 Jun;89(5):1271-82
references.pmid: 15147520
references.citation: J Neurosci. 2000 Aug 1;20(15):5775-81
references.pmid: 10908618