Inhibitors of Protein Kinase C (PKC) Prevent Activated Transcription

Catley, Matthew C.; Cambridge, Lisa; Nasuhara, Yasuyuki; Ito, Kazuhiro; Chivers, Joanna E.; Beaton, Andrew; Holden, Neil S.; Bergmann, Martin; Barnes, Peter J.; Newton, Robert

doi:10.1074/jbc.m400765200

Cited by 75 publications

(51 citation statements)

References 63 publications

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“…Previous studies have shown that NF-B-mediated transcription can be regulated at several levels. Early studies focused on phosphorylation, ubiquitination, and proteasome-mediated degradation of IB␣ and resultant NF-B translocation (18,19). We clearly showed that whereas IB␣ and resultant NF-B translocation occurred in response to TNF-␣, these were not regulated by PKC␤, because PKC␤ inhibition had no effect on NF-B translocation.…”

Section: Discussionmentioning

confidence: 81%

“…The NF-B-dependent luciferase reporter, 6NFBtkluc (18,19), was obtained from R. Newton (University of Calgary, Calgary, Canada). Human WT PKC␤II, catalytically inactive PKC␤II (PKC␤II K371D), and hemagglutinin-WT PKC␤I were from A. Newton (University of California, San Diego, CA); CBP and p300 expression vectors were from D. Chakravarti (University of Pennsylvania, Philadelphia, PA).…”

Section: Reagents and Plasmidsmentioning

confidence: 99%

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PKCβΙΙ Augments NF-κB-Dependent Transcription at the CCL11 Promoter via p300/CBP-Associated Factor Recruitment and Histone H4 Acetylation

Clarke

Sutcliffe

Deacon

et al. 2008

The Journal of Immunology

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The transcription factor NF-κB plays a pivotal role in regulating inflammatory gene expression. Its effects are optimized by various coactivators, including histone acetyltransferases (HATs) such as CREB-binding protein/p300 and p300/CBP-associated factor (p/CAF). The molecular mechanisms regulating cofactor recruitment are poorly understood. In this study, we describe a novel role for protein kinase C (PKC) βΙΙ in augmenting NF-κB-mediated TNF-α-induced transcription of the target gene CCL11 in human airway smooth muscle cells by phosphorylating the HAT p/CAF. Studies using reporters, overexpression strategies, kinase-dead and HAT-defective mutants, and chromatin immunoprecipitation showed that PKCβII activation was not involved in NF-κB translocation, but facilitated NF-κB-mediated CCL11 transcription by colocalizing with and phosphorylating p/CAF, and thereby acetylating histone H4 and promoting p65 association with the CCL11 promoter. The effect was dependent on p/CAF’s HAT activity. Furthermore, mouse embryonic fibroblasts from PKCβ knockout mice showed markedly reduced TNF-α-induced CCL11 expression and NF-κB reporter activity that was restored on PKCβII overexpression, suggesting a critical role for this pathway. These data suggest a novel important biological role for PKCβΙΙ in NF-κB-mediated CCL11 transcription by p/CAF activation and histone H4 acetylation.

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Section: Discussionmentioning

confidence: 81%

Section: Reagents and Plasmidsmentioning

confidence: 99%

PKCβΙΙ Augments NF-κB-Dependent Transcription at the CCL11 Promoter via p300/CBP-Associated Factor Recruitment and Histone H4 Acetylation

Clarke

Sutcliffe

Deacon

et al. 2008

The Journal of Immunology

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“…Recent studies have shown that the p65 subunit is directly phosphorylated by an upstream kinase before activating downstream genes (Catley et al, 2004;Takada et al, 2004b). Based on those results, we tested whether SFN and PEITC could also inhibit the nuclear translocation and phosphorylation Effects of SFN and PEITC on IKKa and IKKb activity.…”

Section: Sfn and Peitc Inhibit The Level Of P65 In The Nucleusmentioning

confidence: 96%

Suppression of NF-κB and NF-κB-regulated gene expression by sulforaphane and PEITC through IκBα, IKK pathway in human prostate cancer PC-3 cells

et al. 2005

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“…EMSA EMSA was performed as described previously (36,37). Briefly, nuclear proteins (5 g) were used in binding reactions.…”

Section: Nf-b Family Nuclear Localization and Dna Binding (Transam)mentioning

confidence: 99%

The Role of IκB Kinase 2, but Not Activation of NF-κB, in the Release of CXCR3 Ligands from IFN-γ-Stimulated Human Bronchial Epithelial Cells

Tudhope

Catley

Fenwick

et al. 2007

The Journal of Immunology

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The severity of chronic obstructive pulmonary disease correlates with increased numbers of cytotoxic CD8+ T lymphocytes in the lung parenchyma. CD8+ T lymphocytes release IFN-γ which stimulates airway epithelial cells to produce CXCR3 chemokines leading to further recruitment of CD8+ T lymphocytes. To evaluate the signaling pathways involved in regulation of CXCR3 ligands, the human bronchial epithelial cell line BEAS-2B was stimulated with IFN-γ and the release of the CXCR3 ligands was measured by ELISA. The release of CXCL9, CXCL10, and CXCL11 was inhibited by an IκB kinase 2 (IKK2) selective inhibitor 2-[(Aminocarbonyl)amino]-5-[4-fluorophenyl]-3-thiophenecarboxamide (TPCA-1) (EC50 values were 0.50 ± 0.03, 0.17 ± 0.06, and 0.45 ± 0.10 μM, respectively (n = 6)) and an IKK1/2 selective inhibitor 2-amino-6-(2′cyclopropylemethoxy-6′-hydroxy-phenyl)-4-piperidin-3-yl-pyridine-3-carbonitrile (EC50 values 0.74 ± 0.40, 0.27 ± 0.06, and 0.88 ± 0.29 μM, respectively (n = 6)). The glucocorticosteroid dexamethasone had no effect on CXCR3 ligand release. The release of CXCL10 was most sensitive to inhibition by IKK2 and a role for IKK2 in CXCL10 release was confirmed by overexpression of dominant-negative adenoviral constructs to IKK2 (68.2 ± 8.3% n = 5), but not of IKK1. Neither phosphorylation of IκBα, translocation of p65 to the nucleus, or activation of a NF-κB-dependent reporter (Ad-NF-κB-luc) were detected following stimulation of BEAS-2B cells with IFN-γ. These data suggest that IKK2 is also involved in the IFN-γ-stimulated release of the CXCR3 ligands through a novel mechanism that is independent NF-κB.

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Inhibitors of Protein Kinase C (PKC) Prevent Activated Transcription

Cited by 75 publications

References 63 publications

PKCβΙΙ Augments NF-κB-Dependent Transcription at the CCL11 Promoter via p300/CBP-Associated Factor Recruitment and Histone H4 Acetylation

PKCβΙΙ Augments NF-κB-Dependent Transcription at the CCL11 Promoter via p300/CBP-Associated Factor Recruitment and Histone H4 Acetylation

Suppression of NF-κB and NF-κB-regulated gene expression by sulforaphane and PEITC through IκBα, IKK pathway in human prostate cancer PC-3 cells

The Role of IκB Kinase 2, but Not Activation of NF-κB, in the Release of CXCR3 Ligands from IFN-γ-Stimulated Human Bronchial Epithelial Cells

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