PMID- 11493922
OWN - NLM
STAT- MEDLINE
DCOM- 20010830
LR  - 20131121
IS  - 0028-0836 (Print)
IS  - 0028-0836 (Linking)
VI  - 412
IP  - 6847
DP  - 2001 Aug 9
TI  - Erythropoietin-mediated neuroprotection involves cross-talk between Jak2 and 
      NF-kappaB signalling cascades.
PG  - 641-7
AB  - Erythropoietin, a kidney cytokine regulating haematopoiesis (the production of 
      blood cells), is also produced in the brain after oxidative or nitrosative 
      stress. The transcription factor hypoxia-inducible factor-1 (HIF-1) upregulates 
      EPO following hypoxic stimuli. Here we show that preconditioning with EPO 
      protects neurons in models of ischaemic and degenerative damage due to 
      excitotoxins and consequent generation of free radicals, including nitric oxide 
      (NO). Activation of neuronal EPO receptors (EPORs) prevents apoptosis induced by 
      NMDA (N-methyl-d-aspartate) or NO by triggering cross-talk between the signalling 
      pathways of Janus kinase-2 (Jak2) and nuclear factor-kappaB (NF-kappaB). We show 
      that EPOR-mediated activation of Jak2 leads to phosphorylation of the inhibitor 
      of NF-kappaB (IkappaB), subsequent nuclear translocation of the transcription 
      factor NF-kappaB, and NF-kappaB-dependent transcription of neuroprotective genes. 
      Transfection of cerebrocortical neurons with a dominant interfering form of Jak2 
      or an IkappaBalpha super-repressor blocks EPO-mediated prevention of neuronal 
      apoptosis. Thus neuronal EPORs activate a neuroprotective pathway that is 
      distinct from previously well characterized Jak and NF-kappaB functions. 
      Moreover, this EPO effect may underlie neuroprotection mediated by 
      hypoxic-ischaemic preconditioning.
FAU - Digicaylioglu, M
AU  - Digicaylioglu M
AD  - Center for Neuroscience and Aging Research, The Burnham Institute, La Jolla, CA 
      92037, USA.
FAU - Lipton, S A
AU  - Lipton SA
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - England
TA  - Nature
JT  - Nature
JID - 0410462
RN  - 0 (NF-kappa B)
RN  - 0 (Neuroprotective Agents)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (Receptors, Erythropoietin)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 11096-26-7 (Erythropoietin)
RN  - 31C4KY9ESH (Nitric Oxide)
RN  - 6384-92-5 (N-Methylaspartate)
RN  - 9007-49-2 (DNA)
RN  - EC 1.15.1.1 (Superoxide Dismutase)
RN  - EC 2.7.10.1 (Protein-Tyrosine Kinases)
RN  - EC 2.7.10.2 (Jak2 protein, rat)
RN  - EC 2.7.10.2 (Janus Kinase 2)
SB  - IM
CIN - Nature. 2001 Aug 9;412(6847):601-2. PMID: 11493905
MH  - Animals
MH  - *Apoptosis
MH  - Cell Nucleus/metabolism
MH  - Cells, Cultured
MH  - DNA/metabolism
MH  - Erythropoietin/metabolism/*physiology
MH  - Genes, Reporter
MH  - Janus Kinase 2
MH  - N-Methylaspartate
MH  - NF-kappa B/*metabolism
MH  - Neurons/*metabolism
MH  - Neuroprotective Agents/metabolism
MH  - Nitric Oxide/metabolism
MH  - Protein Binding
MH  - Protein Transport
MH  - Protein-Tyrosine Kinases/*metabolism
MH  - *Proto-Oncogene Proteins
MH  - Rats
MH  - Receptors, Erythropoietin/metabolism
MH  - Signal Transduction
MH  - Superoxide Dismutase/metabolism
MH  - Tumor Necrosis Factor-alpha/metabolism
EDAT- 2001/08/09 10:00
MHDA- 2001/08/31 10:01
CRDT- 2001/08/09 10:00
PHST- 2001/08/09 10:00 [pubmed]
PHST- 2001/08/31 10:01 [medline]
PHST- 2001/08/09 10:00 [entrez]
AID - 35088074 [pii]
AID - 10.1038/35088074 [doi]
PST - ppublish
SO  - Nature. 2001 Aug 9;412(6847):641-7. doi: 10.1038/35088074.