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Published 14 March 2005. doi:10.1083/jcb.200407079
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 168, Number 6, 911-920
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Article

 Inhibition of NGF deprivation–induced death by low oxygen involves suppression of BIMEL and activation of HIF-1

Liang Xie1, Randall S. Johnson2, and Robert S. Freeman1

1 Department of Pharmacology and Physiology, University of Rochester School of Medicine, Rochester, NY 14642
2 Department of Biology, University of California, San Diego, San Diego, CA 92138

Correspondence to Robert S. Freeman: Robert_Freeman{at}urmc.rochester.edu

Changes in O2 tension can significantly impact cell survival, yet the mechanisms underlying these effects are not well understood. Here, we report that maintaining sympathetic neurons under low O2 inhibits apoptosis caused by NGF deprivation. Low O2 exposure blocked cytochrome c release after NGF withdrawal, in part by suppressing the up-regulation of BIMEL. Forced BIMEL expression removed the block to cytochrome c release but did not prevent protection by low O2. Exposing neurons to low O2 also activated hypoxia-inducible factor (HIF) and expression of a stabilized form of HIF-1{alpha} (HIF-1{alpha}PP->AG) inhibited cell death in normoxic, NGF-deprived cells. Targeted deletion of HIF-1{alpha} partially suppressed the protective effect of low O2, whereas deletion of HIF-1{alpha} combined with forced BIMEL expression completely reversed the ability of low O2 to inhibit cell death. These data suggest a new model for how O2 tension can influence apoptotic events that underlie trophic factor deprivation–induced cell death.

Abbreviations used in this paper: BAF, boc-aspartyl(OMe)-fluoromethylketone; EGLN, egg-laying nine; ERK, extracellular signal-regulated kinase; HIF, hypoxia-inducible factor; HRE, hypoxia response element; JNK, c-Jun NH2-terminal kinase; MOI, multiplicity of infection.


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