The role of JAK-STAT signaling within the CNS

Nicolas, Céline S.; Amici, Mascia; Bortolotto, Zuner A.; Doherty, Andrew J.; Csaba, Zsolt; Fafouri, Assia; Dournaud, Pascal; Gressèns, Pierre; Collingridge, Graham L.; Peineau, Stéphane

doi:10.4161/jkst.22925

Cited by 230 publications

(200 citation statements)

References 96 publications

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“…Although not derived from investigations on neuronal plasticity, the list of nonhistone proteins targeted by HATs from the p300/CBP and MYST families (named for the founding members in yeast: MOZ, YBF2, SAS2 and TIP60) contains candidates such as STAT, NF-kB, steroid receptors, importin-a. They all contribute to processes underlying neuronal plasticity and learning (Nicolas et al 2013;Srivastava et al 2013;Snow et al 2014;Panayotis et al 2015) and therefore qualify as downstream targets of C646.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of different histone acetyltransferases (HATs) uncovers transcription-dependent and -independent acetylation-mediated mechanisms in memory formation

et al. 2016

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Acetylation of histones changes the efficiency of the transcription processes and thus contributes to the formation of longterm memory (LTM). In our comparative study, we used two inhibitors to characterize the contribution of different histone acetyl transferases (HATs) to appetitive associative learning in the honeybee. For one we applied garcinol, an inhibitor of the HATs of the p300 (EP300 binding protein)/CBP (CREB-binding protein) family, and the HATs of the PCAF (p300/ CBP-associated factor) family. As comparative agent we applied C646, a specific inhibitor that selectively blocks HATS of the p300/CBP family. Immunochemical analysis reveals differences in histone H3 acetylation in the honeybee brain, in response to the injection of either C646 or garcinol. Behavioral assessment reveals that the two drugs cause memory impairment of different nature when injected after associative conditioning: processes disturbed by garcinol are annihilated by the established transcription blocker actinomycin D and thus seem to require transcription processes. Actions of C646 are unaltered by actinomycin D, and thus seem to be independent of transcription. The outcome of our different approaches as summarized suggests that distinct HATs contribute to different acetylation-mediated processes in memory formation. We further deduce that the acetylation-mediated processes in memory formation comprise transcription-dependent and transcription-independent mechanisms.

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Section: Discussionmentioning

confidence: 99%

Inhibition of different histone acetyltransferases (HATs) uncovers transcription-dependent and -independent acetylation-mediated mechanisms in memory formation

et al. 2016

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“…3,[5][6][7][8] One of the key regulators of this redox homeostatic network, along with the hypoxia-inducible factors, is the Signal Transducers and Activators of Transcription (STAT) family of proteins. 9 Phosphorylation at specific tyrosine residues and subsequent dimerization is required for STAT activation; the dimers then translocate to the nucleus, where they bind to their target gene's promoter region. 10 STAT-dependent gene regulation has been implicated in a number of pathologies, including several forms of cancer and polycystic kidney disease.…”

Section: Introductionmentioning

confidence: 99%

STAT-Dependent Upregulation of 12/15-Lipoxygenase Contributes to Neuronal Injury after Stroke

Jung

Karataş

Liu

et al. 2015

J Cereb Blood Flow Metab

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Oxidative stress is a major brain injury mechanism after ischemic stroke. 12/15-lipoxygenase (12/15-LOX) is a key mediator of oxidative stress, contributing to neuronal cell death and vascular leakage. Nonetheless, the mechanism leading to its upregulation is currently unknown. We show here that Signal Transducers and Activators of Transcription (STATs), specifically STAT6 and possibly STAT1, increase transcription of 12/15-LOX in neuronal cells. Both p-STAT6 and -1 bound to specific STAT binding sites in the mouse 12/15-LOX promoter. Small interfering RNA (siRNA) knockdown showed STAT6 to be the dominant regulator, reducing 12/15-LOX promoter activation and cell death in oxidatively stressed HT22 cells. STAT6 siRNA efficiently prevented the increase of 12/15-LOX in murine primary neurons, both after induction of oxidative stress and after oxygen-glucose deprivation. Early activation of STAT6 and STAT1 in mice was consistent with a role in regulating 12/15-LOX in focal ischemia. Brains of human stroke patients showed increased p-STAT6 and p-STAT1 in the peri-infarct region, along with 12/15-LOX and markers of apoptosis. These results link STAT6 and STAT1 to the 12/15-LOX damage pathway and suggest disregulation of STAT-dependent transcription as injury mechanism in stroke. Selectively targeting STATs may thus be a novel therapeutic approach to reducing brain injury after a stroke.

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“…Phosphorylation of STAT3 and other STAT proteins occurs primarily through the activation of Janus kinases (JAKs) by cell receptor binding by neurotransmitters, hormones, neurotrophic factors, or other extracellular signaling proteins. A primary cellular function for JAK-STAT signaling is to influence gene expression [47]. Upon activation, JAKs are phosphorylated and this leads to the phosphorylation and dimerization of STAT proteins.…”

Section: Transcription Factor Involvement In Dendritic Plasticitymentioning

confidence: 99%

Transcriptional and Epigenetic Regulation in Injury-Mediated Neuronal Dendritic Plasticity

Wang

et al. 2016

Neurosci. Bull.

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Injury to the nervous system induces localized damage in neural structures and neuronal death through the primary insult, as well as delayed atrophy and impaired plasticity of the delicate dendritic fields necessary for interneuronal communication. Excitotoxicity and other secondary biochemical events contribute to morphological changes in neurons following injury. Evidence suggests that various transcription factors are involved in the dendritic response to injury and potential therapies. Transcription factors play critical roles in the intracellular regulation of neuronal morphological plasticity and dendritic growth and patterning. Mounting evidence supports a crucial role for epigenetic modifications via histone deacetylases, histone acetyltransferases, and DNA methyltransferases that modify gene expression in neuronal injury and repair processes. Gene regulation through epigenetic modification is of great interest in neurotrauma research, and an early picture is beginning to emerge concerning how injury triggers intracellular events that modulate such responses. This review provides an overview of injury-mediated influences on transcriptional regulation through epigenetic modification, the intracellular processes involved in the morphological consequences of such changes, and potential approaches to the therapeutic manipulation of neuronal epigenetics for regulating gene expression to facilitate growth and signaling through dendritic arborization following injury.

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The role of JAK-STAT signaling within the CNS

Cited by 230 publications

References 96 publications

Inhibition of different histone acetyltransferases (HATs) uncovers transcription-dependent and -independent acetylation-mediated mechanisms in memory formation

Inhibition of different histone acetyltransferases (HATs) uncovers transcription-dependent and -independent acetylation-mediated mechanisms in memory formation

STAT-Dependent Upregulation of 12/15-Lipoxygenase Contributes to Neuronal Injury after Stroke

Transcriptional and Epigenetic Regulation in Injury-Mediated Neuronal Dendritic Plasticity

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