LIM domain only 4 protein promotes granulocyte colony-stimulating factor-induced signaling in neurons |
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Authors: | Mariana Gomez-Smith Zhaohong Qin Xun Zhou Sarah C Schock Hsiao-Huei Chen |
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Institution: | (1) Ottawa Hospital Research Institute (Neuroscience), University of Ottawa, Ottawa, ON, Canada;(2) Centre for Stroke Recovery, University of Ottawa, Ottawa, ON, Canada;(3) Department of Medicine, University of Ottawa, Ottawa, ON, Canada;(4) Ottawa Health Research Institute (Neuroscience), University of Ottawa, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada; |
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Abstract: | Granulocyte colony-stimulating factor (GCSF) is currently in clinical trials to treat neurodegenerative diseases and stroke.
Here, we tested whether LIM domain only 4 protein (LMO4), a hypoxia-inducible gene that protects neurons from ischemic injury,
could modulate the neuroprotective effect of GCSF. We showed that GCSF treatment acetylates and phosphorylates Stat3, activates
expression of a Stat3-dependent anti-apoptotic gene, p27, and increases neuron survival from ischemic injury. LMO4 participates
in Stat3 signaling in hepatocytes and associates with histone deacetylase 2 (HDAC2) in cancer cells. In the absence of LMO4,
GCSF fails to rescue neurons from ischemic insults. In wild-type neurons, inhibition of HDAC promoted Stat3 acetylation and
the antiapoptotic effect of GCSF. In LMO4 null cortical neurons, expression of wild-type but not HDAC-interaction-deficient
LMO4 restored GCSF-induced Stat3 acetylation and p27 expression. Thus, our results indicate that LMO4 enhances GCSF-induced
Stat3 signaling in neurons, in part by sequestering HDAC. |
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