Role of STAT3 and PI 3-Kinase/Akt in Mediating the Survival Actions of Cytokines on Sensory Neurons

Alonzi, Tonino; Middleton, Gayle; Wyatt, Sean; Buchman, Vladimir L.; Betz, Ulrich; Müller, Werner; Musiani, Piero; Poli, Valeria; Davies, Alun M.

doi:10.1006/mcne.2001.1018

Cited by 129 publications

(96 citation statements)

References 68 publications

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“…Also, we have demonstrated for the first time that leptin and amylin increase STAT3/AMPK/ERK signalling and that the effects of these two hormones are similar in magnitude, peaking at about the same time in mouse GT1-7 hypothalamic and C 2 C 12 muscle cell lines in vitro [35] and in human adipose tissues and peripheral blood mononuclear cells ex vivo [30]. Moreover, it has been proposed that STAT3/AMPK/ERK signalling is important for the maintenance of neural development [37][38][39][40]. Based on these results, we checked whether leptin may interact with amylin and whether administration of amylin and leptin in combination could further increase leptinstimulated STAT3/AMPK/ERK signalling in mouse HT19-7 HN cells.…”

Section: Discussionmentioning

confidence: 99%

Amylin-induced downregulation of hippocampal neurogenesis is attenuated by leptin in a STAT3/AMPK/ERK-dependent manner in mice

2012

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Aims/hypothesis Both leptin and insulin sensitivity have been linked with pathophysiological processes involving the central nervous system in general, and the hippocampus in particular, but the role of leptin in hippocampal neurogenesis has not yet been elucidated. Also, no previous studies have evaluated whether amylin or the endogenous insulin sensitiser adiponectin interact with leptin to alter hippocampal neurogenesis in mouse hippocampal neuronal (HN) cells or investigated the role of leptin, amylin or adiponectin signalling in mouse HN cells. Methods Hippocampal neurogenesis and leptin, amylin and adiponectin signalling were studied in vitro using mouse H19-7 HN cell lines. Results Amylin decreased cell proliferation in a dosedependent manner. This effect was diminished by leptin administration and was dependent on signal transducer and activator of transcription 3 (STAT3)/AMP-activated protein kinase (AMPK)/extracellular signal-regulated kinase (ERK). Adiponectin effects were null. We also observed, using immunocytochemical analysis, that amylin decreased activation of microtubule-associated protein 2, a specific neurite outgrowth marker, and synapsin, a specific synaptogenesis marker. By contrast, both effects were attenuated by co-administration of leptin. Finally, we observed that these effects were blocked by pre-treatment with AG490, a STAT3 inhibitor, and STAT3 small interfering RNA administration. Conclusions/interpretation Our data suggest that amylin in pharmacological concentrations may have a neurotoxic effect whereas leptin in physiological and pharmacological concentrations has a protective effect counteracting amylindecreased hippocampal neurogenesis via STAT3/AMPK/ ERK signalling in mouse H19-7 HN cell lines. Overall, our data support a novel role for leptin and amylin in the processes of mouse hippocampal neurogenesis and provide new insights into the mechanisms of neurogenic regulation.

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Section: Discussionmentioning

confidence: 99%

Amylin-induced downregulation of hippocampal neurogenesis is attenuated by leptin in a STAT3/AMPK/ERK-dependent manner in mice

2012

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“…In some cases, the action of STAT3 seems to be ascribed to the induction of a set of important target genes, but in others, it may be acting as a repressor (e.g., in the thymic epithelium) (17,33) or as a signaling adaptor without a transcriptional function (e.g., activation of Akt in neurons) (17,34). In the nuclear translocation assay, low level of tyrosine phosphorylated STAT3 was observed in the nuclei but was independent of insulin ( Fig.…”

Section: Stat3 Sensitizes Insulin Signalingmentioning

confidence: 99%

STAT3 Sensitizes Insulin Signaling by Negatively Regulating Glycogen Synthase Kinase-3β

Moh

Zhang

et al. 2008

Diabetes

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OBJECTIVE-Glucose homeostasis is achieved by triggering regulation of glycogen synthesis genes in response to insulin when mammals feed, but the underlying molecular mechanism remains largely unknown. The aim of our study was to examine the role of the signal transducers and activators of transcription 3 (STAT3) in insulin signaling.RESEARCH DESIGN AND METHODS-We generated a strain of mice carrying a targeted disruption of Stat3 gene in the liver (L-Stat3 Ϫ/Ϫ mice). Hepatocytes of the L-Stat3 Ϫ/Ϫ mice were isolated to establish cell lines for mechanistic studies. Nuclear translocation and DNA-protein interaction of STAT3 was analyzed with immunofluorescent and chromatin immunoprecipitation methods, respectively. Levels of glucose, insulin, leptin, and glucagon were profiled, and putative downstream molecules of STAT3 were examined in the presence of various stimuli in L-Stat3 Ϫ/Ϫ and control mice. RESULTS-STAT3was found to sensitize the insulin signaling through suppression of GSK-3␤, a negative regulator of insulin signaling pathway. During feeding, both mRNA and protein levels of GSK-3␤ decreased in Stat3 f/ϩ mice, which reflected the need of hepatocytes for insulin to induce glycogen synthesis. In contrast, the L-Stat3 Ϫ/Ϫ mice lost this control and showed a monophasic increase in the GSK-3␤ level in response to insulin. Administration of GSK-3␤ inhibitors lithium chloride and L803-mts restored glucose homeostasis and rescued the glucose intolerance and impaired insulin response in L-Stat3 Ϫ/Ϫ mice.CONCLUSIONS-These data indicate that STAT3 sensitizes insulin signaling by negatively regulating GSK-3␤. Inactivation of STAT3 in the liver contributes significantly to the pathogenesis of insulin resistance.

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“…Complex Directly Enhances Neuronal Viability-Activation of the JAK/STAT pathway mediates, to a great extent, the neuroprotective effects of IL-6 family member cytokines, including CNTF (19). To examine whether Complex can activate this pathway in neurons (as it does in astrocytes) (18), we assessed the effects of Complex on the levels of tyrosine 705-phosphorylated STAT3 (pSTAT3) in our neuron cultures.…”

Section: Resultsmentioning

confidence: 99%

“…This finding may be explained by the critical requirement of functional JAK/STAT signaling in development and by its prominent role in cell survival (19,66). The small population of young MAP2-positive neurons that remained viable in the presence of AG490 exhibited fewer, shorter, unbranched neurites.…”

Section: Discussionmentioning

confidence: 98%

“…Following injury-induced release, CNTF and soluble CNTFR␣ together form a heterodimer (hereafter referred to as "Complex") that can interact with the ubiquitously expressed ␤-receptor subunits, glycoprotein 130 (gp130) and leukemia inhibitory factor receptor ␤ (LIFR␤) (14,17,18). The subsequent heterodimerization of gp130 and LIFR␤ activates several signaling cascades, including the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway (19). In addition, we have recently found that Complex increases both the expression of the gap junctional constituent connexin43 and intercellular coupling in glia via trans-signaling (17,18), the term used to describe the ability of a ligand to bind a soluble receptor (␣ subunit), which subsequently associates with the ␤ subunits of the receptor on cells that do not normally express the ␣-receptor of the ligand (20).…”

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confidence: 99%

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Co-administration of Ciliary Neurotrophic Factor with Its Soluble Receptor Protects against Neuronal Death and Enhances Neurite Outgrowth

Ozog¹,

Modha

Church

et al. 2008

Journal of Biological Chemistry

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Attempts to promote neuronal survival and repair with ciliary neurotrophic factor (CNTF) have met with limited success. The variability of results obtained with CNTF may, in part, reflect the fact that some of the biological actions of the cytokine are mediated by a complex formed between CNTF and its specific receptor, CNTFR␣, which exists in both membrane-bound and soluble forms. In this study, we compared the actions of CNTF alone and CNTF complexed with soluble CNTFR␣ (hereafter termed "Complex") on neuronal survival and growth. Although CNTF alone produced limited effects, Complex protected against glutamate-mediated excitotoxicity via gap junction-dependent and -independent mechanisms. Further examination revealed that only Complex promoted neurite outgrowth. Differential gene expression analysis revealed that, compared with CNTF alone, Complex differentially regulates several neuroprotective and neurotrophic genes. Collectively, these findings indicate that CNTF exerts more robust effects on neuronal survival and growth when applied in combination with its soluble receptor.

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Role of STAT3 and PI 3-Kinase/Akt in Mediating the Survival Actions of Cytokines on Sensory Neurons

Cited by 129 publications

References 68 publications

Amylin-induced downregulation of hippocampal neurogenesis is attenuated by leptin in a STAT3/AMPK/ERK-dependent manner in mice

Amylin-induced downregulation of hippocampal neurogenesis is attenuated by leptin in a STAT3/AMPK/ERK-dependent manner in mice

STAT3 Sensitizes Insulin Signaling by Negatively Regulating Glycogen Synthase Kinase-3β

Co-administration of Ciliary Neurotrophic Factor with Its Soluble Receptor Protects against Neuronal Death and Enhances Neurite Outgrowth

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