Role of STAT3 and PI 3-kinase/Akt in mediating the survival actions of cytokines on sensory neurons.
The binding of cytokines to the gp130 receptor activates the STAT3, MEK/MAPK, and PI3K/Akt signalling pathways. To assess the relative importance of these pathways in promoting the survival of cytokine-dependent neurons, we conditionally inactivated STAT3 in mice and inhibited MEK, PI3K, and Akt in cultured neurons using pharmacological reagents and by expressing specific inhibitory proteins. Inactivation of STAT3 enhanced the death of the cytokine-dependent sensory neurons of the nodose ganglion in vivo and substantially reduced the response of these neurons to CNTF and LIF in vitro. LY294002, an inhibitor of PI3K, but not PD98059, an inhibitor of MEK, markedly reduced the response of these neurons to CNTF, as did dominant-negative PI3K, dominant-negative Akt, and overexpression of Ruk (a natural PI3K inhibitor). These results demonstrate that STAT3 and PI3K/Akt signalling play major roles in mediating the survival response of neurons to cytokines.
Alonzi
T
T
School of Life Sciences, Wellcome Trust Biocentre, University of Dundee, Dow Street, Dundee, DD1 5EH, Scotland.
Middleton
G
G
Wyatt
S
S
Buchman
V
V
Betz
U A
UA
Müller
W
W
Musiani
P
P
Poli
V
V
Davies
A M
AM
D000818:Animals; D002470:Cell Survival / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D020934:Ciliary Neurotrophic Factor / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism* / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D017353:Gene Deletion; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009025:Morpholines / Q000494:pharmacology; D009475:Neurons, Afferent / Q000187:drug effects* / Q000502:physiology; D009620:Nodose Ganglion / Q000187:drug effects / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D002867:Chromones; D020934:Ciliary Neurotrophic Factor; D016207:Cytokines; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D050796:STAT3 Transcription Factor; D015534:Trans-Activators; C494087:Stat3 protein, mouse; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one