Extracellular ATP-dependent upregulation of the transcription cofactor LMO4 promotes neuron survival from hypoxia.
Extracellular ATP is elevated by transient ischemia and is a potent signaling molecule in the central nervous system. ATP promotes neuron survival from serum starvation by activating P2Y purinergic receptors. ATP also activates IL-6 production and phosphorylation of Stat3 that promotes neuron survival. The transcription cofactor LMO4 is a positive mediator of IL-6/Stat3 signaling. Here, we found that LMO4 and the pro-survival factor cIAP2 (cellular inhibitor of apoptosis protein 2) are rapidly upregulated in neurons exposed to elevated extracellular ATP. Blocking LMO4 upregulation using siRNA in F11 cells blunted cIAP2 upregulation and abolished the early protective effect of ATP. Similar results were obtained using primary cortical neurons from LMO4 null mice, suggesting that LMO4 is required for ATP to protect neurons from hypoxia-induced apoptosis. Whereas increased Stat3 phosphorylation occurs after LMO4 and cIAP2 induction, the rapid upregulated phosphorylation of ERK and CREB may account for increased LMO4 and cIAP2 by ATP. ATP signaling through ERK and CREB activated LMO4 promoters and ERK activation increased LMO4 protein stability in F11 cells. Taken together, our studies reveal that LMO4 is a rapidly induced downstream effector of ATP signaling that promotes neuron survival from hypoxia.
Chen
Hsiao-Huei
HH
Ottawa Health Research Institute, Ottawa, Ontario, Canada. hchen@uottawa.ca
Schock
Sarah C
SC
Xu
Jin
J
Safarpour
Farzaneh
F
Thompson
Charlie S
CS
Stewart
Alexandre F R
AF
D048868:Adaptor Proteins, Signal Transducing; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D002470:Cell Survival; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D000860:Hypoxia; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D060588:LIM Domain Proteins; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D051381:Rats; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D018398:Homeodomain Proteins; D051034:Inhibitor of Apoptosis Proteins; D060588:LIM Domain Proteins; C491976:Lmo4 protein, mouse; C489787:MAP2 protein, rat; D008869:Microtubule-Associated Proteins; D050796:STAT3 Transcription Factor; D014157:Transcription Factors; D000255:Adenosine Triphosphate; D017868:Cyclic AMP-Dependent Protein Kinases; D048049:Extracellular Signal-Regulated MAP Kinases