Genome-wide mechanisms of Smad binding

Morikawa, Masato; Koinuma, Daizo; Miyazono, Kohei; Heldin, Carl‐Henrik

doi:10.1038/onc.2012.191

Cited by 96 publications

(117 citation statements)

References 81 publications

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“…Although there have been many studies on the role played by Smads in the expression of genes (Matsuzaki, 2013;Morikawa et al, 2013), there are none for GAG genes showing the definitive involvement of these transcription factors. Indeed the current favoured hypothesis is that linker region phosphorylation of Smad2/3 prevents the translocation of the Smad entity to the nucleus whereas our data indicates a correlation between the phosphorylation status of the linker region and increased expression of GAG elongation genes.…”

Section: Discussionmentioning

confidence: 99%

Flavopiridol Inhibits TGF-β-Stimulated Biglycan Synthesis by Blocking Linker Region Phosphorylation and Nuclear Translocation of Smad2

Rostam

Shajimoon

Kamato

et al. 2018

J Pharmacol Exp Ther

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Section: Discussionmentioning

confidence: 99%

Flavopiridol Inhibits TGF-β-Stimulated Biglycan Synthesis by Blocking Linker Region Phosphorylation and Nuclear Translocation of Smad2

Rostam

Shajimoon

Kamato

et al. 2018

J Pharmacol Exp Ther

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“…A single SBE is not sufficient to bind an activated SMAD complex, and, in vivo, SBEs have been shown to occur as direct or inverted ( palindromic) repeats in the regulatory regions of TGF-b/NODAL/activin target genes by promoter analysis, or by whole-genome approaches, such as chromatin immunoprecipitation (ChIP)-sequencing or ChIP-on-chip analysis (Fig. 1A) (Dennler et al 1998;Wong et al 1999;Koinuma et al 2009a;Liu et al 2011;Mullen et al 2011;Morikawa et al 2013).…”

Section: Dna Binding Of Smad Complexes and Its Regulation By Posttranmentioning

confidence: 99%

Transcriptional Control by the SMADs

Hill

2016

Cold Spring Harb Perspect Biol

282

256

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The transforming growth factor-b (TGF-b) family of ligands elicit their biological effects by initiating new programs of gene expression. The best understood signal transducers for these ligands are the SMADs, which essentially act as transcription factors that are activated in the cytoplasm and then accumulate in the nucleus in response to ligand induction where they bind to enhancer/promoter sequences in the regulatory regions of target genes to either activate or repress transcription. This review focuses on the mechanisms whereby the SMADs achieve this and the functional implications. The SMAD complexes have weak affinity for DNA and limited specificity and, thus, they cooperate with other site-specific transcription factors that act either to actively recruit the SMAD complexes or to stabilize their DNA binding. In some situations, these cooperating transcription factors function to integrate the signals from TGF-b family ligands with environmental cues or with information about cell lineage. Activated SMAD complexes regulate transcription via remodeling of the chromatin template. Consistent with this, they recruit a variety of coactivators and corepressors to the chromatin, which either directly or indirectly modify histones and/or modulate chromatin structure.

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“…However, whereas both subunits of the TGF-bR are expressed at higher levels in microglia, the expression, phosphorylation, and nuclear translocation of SMAD2/3 are significantly more abundant in astrocytes. Together with our findings that the SMAD3-specific inhibitor SIS3 markedly suppressed the upregulation of IL-6 in astrocytes, we suggest that SMAD3 is required for the enhanced expression of IL-6 in astrocytes presumably via direct binding to SMAD-binding elements in the IL-6 promoter region (28,37,38). The signals triggering SMAD3 expression and the molecular pathway of p-SMAD3-induced IL-6 upregulation, alone or with additional cofactors (37,39), are yet to be characterized.…”

Section: Discussionmentioning

confidence: 67%

“…Additional support for SMAD2/3-mediated IL-6 upregulation comes from analyzing the promoter region of IL-6 for SMADbinding elements (see review in Ref. 28). We identified several putative SMAD3/4-binding sequences such as GTCT, AGAC, and CAGAC up to 2000 bp upstream to the IL-6 coding sequence.…”

Section: Tgf-b1-induced Il-6 Expression Is Astrocyte-specific and Smamentioning

confidence: 99%

Differential TGF-β Signaling in Glial Subsets Underlies IL-6–Mediated Epileptogenesis in Mice

Levy

Milikovsky

Baranauskas

et al. 2015

The Journal of Immunology

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TGF-β1 is a master cytokine in immune regulation, orchestrating both pro- and anti-inflammatory reactions. Recent studies show that whereas TGF-β1 induces a quiescent microglia phenotype, it plays a pathogenic role in the neurovascular unit and triggers neuronal hyperexcitability and epileptogenesis. In this study, we show that, in primary glial cultures, TGF-β signaling induces rapid upregulation of the cytokine IL-6 in astrocytes, but not in microglia, via enhanced expression, phosphorylation, and nuclear translocation of SMAD2/3. Electrophysiological recordings show that administration of IL-6 increases cortical excitability, culminating in epileptiform discharges in vitro and spontaneous seizures in C57BL/6 mice. Intracellular recordings from layer V pyramidal cells in neocortical slices obtained from IL-6–treated mice show that during epileptogenesis, the cells respond to repetitive orthodromic activation with prolonged after-depolarization with no apparent changes in intrinsic membrane properties. Notably, TGF-β1–induced IL-6 upregulation occurs in brains of FVB/N but not in brains of C57BL/6 mice. Overall, our data suggest that TGF-β signaling in the brain can cause astrocyte activation whereby IL-6 upregulation results in dysregulation of astrocyte–neuronal interactions and neuronal hyperexcitability. Whereas IL-6 is epileptogenic in C57BL/6 mice, its upregulation by TGF-β1 is more profound in FVB/N mice characterized as a relatively more susceptible strain to seizure-induced cell death.

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Genome-wide mechanisms of Smad binding

Cited by 96 publications

References 81 publications

Flavopiridol Inhibits TGF-β-Stimulated Biglycan Synthesis by Blocking Linker Region Phosphorylation and Nuclear Translocation of Smad2

Flavopiridol Inhibits TGF-β-Stimulated Biglycan Synthesis by Blocking Linker Region Phosphorylation and Nuclear Translocation of Smad2

Transcriptional Control by the SMADs

Differential TGF-β Signaling in Glial Subsets Underlies IL-6–Mediated Epileptogenesis in Mice

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