JNK1 Inhibits GluR1 Expression and GluR1-Mediated Calcium Influx through Phosphorylation and Stabilization of Hes-1

Lin, Chia‐Hua; Lee, Eminy H.Y.

doi:10.1523/jneurosci.3380-11.2012

Cited by 30 publications

(28 citation statements)

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“…S8), suggest a decrease in Hes1 protein stability. Although we did not examine the mechanism of this observed decrease in Hes1 protein levels, Hes1 protein is known to be stabilized by phosphorylation (37) or targeted for degradation by interaction with Hes6 (38). Our results suggest a combination of increased NF-κB activation with decreased Hes1-mediated immune suppression in Tle1 Δ/Δ macrophages might be responsible for enhanced sensitivity of Tle1 Δ/Δ BM to LPS-induced inflammation.…”

Section: Discussionmentioning

confidence: 70%

Tle1 tumor suppressor negatively regulates inflammation in vivo and modulates NF-κB inflammatory pathway

Ramasamy

Sáez

Mukhopadhyay

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Tle1 (transducin-like enhancer of split 1) is a corepressor that interacts with a variety of DNA-binding transcription factors and has been implicated in many cellular functions; however, physiological studies are limited. Tle1-deficient (Tle1 Δ/Δ ) mice, although grossly normal at birth, exhibit skin defects, lung hypoplasia, severe runting, poor body condition, and early mortality. Tle1 Δ/Δ mice display a chronic inflammatory phenotype with increased expression of inflammatory cytokines and chemokines in the skin, lung, and intestine and increased circulatory IL-6 and G-CSF, along with a hematopoietic shift toward granulocyte macrophage progenitor and myeloid cells. Tle1 Δ/Δ macrophages produce increased inflammatory cytokines in response to Toll-like receptor (TLR) agonists and lipopolysaccharides (LPS), and Tle1 Δ/Δ mice display an enhanced inflammatory response to ear skin 12-O-tetradecanoylphorbol-13-acetate treatment. Loss of Tle1 not only results in increased phosphorylation and activation of proinflammatory NF-κB but also results in decreased Hes1 (hairy and enhancer of split-1), a negative regulator of inflammation in macrophages. Furthermore, Tle1 Δ/Δ mice exhibit accelerated growth of B6-F10 melanoma xenografts. Our work provides the first in vivo evidence, to our knowledge, that TLE1 is a major counterregulator of inflammation with potential roles in a variety of inflammatory diseases and in cancer progression.T ransducin-like enhancer of split 1 (TLE1) belongs to a family of corepressor proteins called transducin-like enhancer of split, or TLEs. Groucho, the TLE homolog in Drosophila, has crucial roles in neurogenesis, segmentation, and sex determination (1). These corepressors do not bind directly to DNA but rather interact with many different classes of transcription factors and help create a repressor complex (1, 2).Vertebrates express five different TLEs (TLE1-4, AES), although the distinct functions of each of the TLEs has not been well determined. TLE1, the most studied among the Groucho family proteins in mammalian systems, is widely expressed in different tissues and cell types and has been implicated in neuronal differentiation (3, 4) and pancreatic beta cell development (5). TLE1 has tumor suppressor activity (6-8) as well as oncogenic functions in cancer (9, 10). TLE1 associates with many important transcription factors integral for cell proliferation and differentiation, including Runx2 to block rRNA expression (11), HES1 to suppresses MASH2 expression (12), and TCF/LEF proteins to block Wnt target gene activation (13). TLE1 also represses NF-κB activity (14,15). Involvement in these diverse cellular functions and diseases was studied primarily in vitro or using in vivo overexpression systems. The major physiological function of TLE1, however, remains poorly understood.A few recent studies suggest TLE1 might regulate immune function. For example, a single noncoding nucleotide polymorphism within the TLE1 locus was associated with inflammatory bowel diseases (16), and in human monocytes,...

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Section: Discussionmentioning

confidence: 70%

Tle1 tumor suppressor negatively regulates inflammation in vivo and modulates NF-κB inflammatory pathway

Ramasamy

Sáez

Mukhopadhyay

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…These include GRIA1 (glutamate receptor 1), which is a member of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor family of ionotropic glutamate receptors that are critical to synaptic plasticity [50,51]; and DLG2 (disks large homolog 2), which is a critical postsynaptic protein scaffold of excitatory synapses that interacts with NMDA receptor subunits and potassium channels [52,53]. Of further note, GRIA1 is amongst the genes within the 108 loci associated with schizophrenia risk by GWAS studies with a p value of 1.06 × 10 -10 [54].…”

Section: Resultsmentioning

confidence: 99%

WNT/β-Catenin Pathway and Epigenetic Mechanisms Regulate the Pitt-Hopkins Syndrome and Schizophrenia Risk Gene TCF4

et al. 2017

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Genetic variation within the transcription factor TCF4 locus can cause the intellectual disability and developmental disorder Pitt-Hopkins syndrome (PTHS), whereas single-nucleotide polymorphisms within noncoding regions are associated with schizophrenia. These genetic findings position TCF4 as a link between transcription and cognition; however, the neurobiology of TCF4 remains poorly understood. Here, we quantitated multiple distinct TCF4 transcript levels in human induced pluripotent stem cell-derived neural progenitors and differentiated neurons, and PTHS patient fibroblasts. We identify two classes of pharmacological treatments that regulate TCF4 expression: WNT pathway activation and inhibition of class I histone deacetylases. In PTHS fibroblasts, both of these perturbations upregulate a subset of TCF4 transcripts. Finally, using chromatin immunoprecipitation sequencing in conjunction with genome-wide transcriptome analysis, we identified TCF4 target genes that may mediate the effect of TCF4 loss on neuroplasticity. Our studies identify new pharmacological assays, tools, and targets for the development of therapeutics for cognitive disorders.

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“…These JNK substrates encompass members of many different families, including those of the bZIP (Jun, ATF2, Myc [164,224,[229][230][231]), bHLH (Hes1, Twist1 [232,233]), Zinc finger (Sp1 [234]), Forkhead (FOXO4, FOXO3 [235][236][237]), and RUNT (p53, p73 [238,239]) families, as well as proteins of the nuclear receptor family (androgen receptor, glucocorticoid receptor, peroxisome proliferator-activated receptors, RAR␣, and RXR␣ [240][241][242][243][244][245]). Coactivators and corepressors lacking a direct DNA-binding capacity (such as YAP1 [246]) can also be targeted by JNK.…”

Section: Major Classes Of Proteins Targeted By Jnksmentioning

confidence: 99%

“…Therefore, Ser68 phosphorylation may control the nuclear translocation of Twist1 (which is known to be potentiated by epidermal growth factor stimulation), to which Twist1 stabilization might be a secondary effect (366). In the case of the bHLH transcription factor Hes1, JNK-dependent phosphorylation of Ser263 within its flexible C terminus resulted in its stabilization (232). While the phosphorylation site itself is not strictly conserved in all vertebrates, the di-rectly adjacent (extended WRPW-type) Groucho corepressorbinding motif is always preserved (367).…”

Section: Complex Effects Of Jnk On Its Substratesmentioning

confidence: 99%

JNK Signaling: Regulation and Functions Based on Complex Protein-Protein Partnerships

Zeke

Misheva

Reményi

et al. 2016

Microbiol Mol Biol Rev

409

350

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SUMMARYThe c-Jun N-terminal kinases (JNKs), as members of the mitogen-activated protein kinase (MAPK) family, mediate eukaryotic cell responses to a wide range of abiotic and biotic stress insults. JNKs also regulate important physiological processes, including neuronal functions, immunological actions, and embryonic development, via their impact on gene expression, cytoskeletal protein dynamics, and cell death/survival pathways. Although the JNK pathway has been under study for >20 years, its complexity is still perplexing, with multiple protein partners of JNKs underlying the diversity of actions. Here we review the current knowledge of JNK structure and isoforms as well as the partnerships of JNKs with a range of intracellular proteins. Many of these proteins are direct substrates of the JNKs. We analyzed almost 100 of these target proteins in detail within a framework of their classification based on their regulation by JNKs. Examples of these JNK substrates include a diverse assortment of nuclear transcription factors (Jun, ATF2, Myc, Elk1), cytoplasmic proteins involved in cytoskeleton regulation (DCX, Tau, WDR62) or vesicular transport (JIP1, JIP3), cell membrane receptors (BMPR2), and mitochondrial proteins (Mcl1, Bim). In addition, because upstream signaling components impact JNK activity, we critically assessed the involvement of signaling scaffolds and the roles of feedback mechanisms in the JNK pathway. Despite a clarification of many regulatory events in JNK-dependent signaling during the past decade, many other structural and mechanistic insights are just beginning to be revealed. These advances open new opportunities to understand the role of JNK signaling in diverse physiological and pathophysiological states.

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JNK1 Inhibits GluR1 Expression and GluR1-Mediated Calcium Influx through Phosphorylation and Stabilization of Hes-1

Cited by 30 publications

References 50 publications

Tle1 tumor suppressor negatively regulates inflammation in vivo and modulates NF-κB inflammatory pathway

Tle1 tumor suppressor negatively regulates inflammation in vivo and modulates NF-κB inflammatory pathway

WNT/β-Catenin Pathway and Epigenetic Mechanisms Regulate the Pitt-Hopkins Syndrome and Schizophrenia Risk Gene TCF4

JNK Signaling: Regulation and Functions Based on Complex Protein-Protein Partnerships

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