LIM domain only 4 protein promotes granulocyte colony-stimulating factor-induced signaling in neurons.
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.
Gomez-Smith
Mariana
M
Ottawa Hospital Research Institute, University of Ottawa, ON, Canada.
Qin
Zhaohong
Z
Zhou
Xun
X
Schock
Sarah C
SC
Chen
Hsiao-Huei
HH
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002478:Cells, Cultured; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism; D056464:Histone Deacetylase 2 / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D060588:LIM Domain Proteins; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D018398:Homeodomain Proteins; D060588:LIM Domain Proteins; C491976:Lmo4 protein, mouse; D014157:Transcription Factors; D016179:Granulocyte Colony-Stimulating Factor; C533424:Hdac2 protein, mouse; D056464:Histone Deacetylase 2