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The Journal of Immunology, 2008, 181, 3503-3514
Copyright © 2008 by The American Association of Immunologists, Inc.
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PKCβII Augments NF-{kappa}B-Dependent Transcription at the CCL11 Promoter via p300/CBP-Associated Factor Recruitment and Histone H4 Acetylation1

Deborah L. Clarke, Amy Sutcliffe, Karl Deacon, Dawn Bradbury, Lisa Corbett and Alan J. Knox2

Division of Respiratory Medicine, University of Nottingham, City Hospital, Nottingham, United Kingdom

The transcription factor NF-{kappa}B 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) βII in augmenting NF-{kappa}B-mediated TNF-{alpha}-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-{kappa}B translocation, but facilitated NF-{kappa}B-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-{alpha}-induced CCL11 expression and NF-{kappa}B reporter activity that was restored on PKCβII overexpression, suggesting a critical role for this pathway. These data suggest a novel important biological role for PKCβII in NF-{kappa}B-mediated CCL11 transcription by p/CAF activation and histone H4 acetylation.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 D.L.C. and A.J.K. were supported by a grant from The Wellcome Trust.

2 Address correspondence and reprint requests to Dr. Alan J. Knox, Division of Respiratory Medicine, Clinical Sciences Building, City Hospital, Nottingham, NG5 1PB U.K. E-mail address: alan.knox{at}nottingham.ac.uk

3 Abbreviations used in this paper: IKK, I{kappa}B kinase; Bis I, bisindolylmaleimide I; CBP, CREB-binding protein; ChIP, chromatin immunoprecipitation; COX-2, cyclooxygenase-2; EGR-1, early growth response-1; HASM, human airway smooth muscle; HAT, histone acetyltransferase; HDAC, histone deacetylase; MEF, mouse embryonic fibroblast; p/CAF, p300/CBP-associated factor; PKC, protein kinase C; WT, wild type.






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