The endoplasmic reticulum stress response factor CHOP-10 protects against hypoxia-induced neuronal death.
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.
Halterman
Marc W
MW
Department of Neurology, University of Rochester Medical Center, Rochester, New York 14642, USA. marc_halterman@urmc.rochester.edu
Gill
Molly
M
DeJesus
Chris
C
Ogihara
Mitsunori
M
Schor
Nina F
NF
Federoff
Howard J
HJ
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*
C497250:Ddit3 protein, mouse; D051742:Transcription Factor CHOP; D019284:Thapsigargin
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