PKCbetaII augments NF-kappaB-dependent transcription at the CCL11 promoter via p300/CBP-associated factor recruitment and histone H4 acetylation

The transcription factor NF-kappaB 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 regula...

Full description

Saved in:
Bibliographic Details
Published in:The Journal of immunology (1950) 2008-09, Vol.181 (5), p.3503-3514
Main Authors: Clarke, Deborah L, Sutcliffe, Amy, Deacon, Karl, Bradbury, Dawn, Corbett, Lisa, Knox, Alan J
Format: Article
Language:English
Subjects:
Acetylation
Adult
Animals
Cells, Cultured
Chemokine CCL11 - genetics
E1A-Associated p300 Protein - metabolism
Female
Histones - metabolism
Humans
Male
Mice
Middle Aged
Myocytes, Smooth Muscle
NF-kappa B - physiology
Promoter Regions, Genetic
Protein Kinase C - physiology
Protein Kinase C beta
Protein Transport
Respiratory System
Transcription Factor RelA - physiology
Transcription, Genetic
Tumor Necrosis Factor-alpha
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:The transcription factor NF-kappaB 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) betaIotaIota in augmenting NF-kappaB-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 PKCbetaII activation was not involved in NF-kappaB translocation, but facilitated NF-kappaB-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 PKCbeta knockout mice showed markedly reduced TNF-alpha-induced CCL11 expression and NF-kappaB reporter activity that was restored on PKCbetaII overexpression, suggesting a critical role for this pathway. These data suggest a novel important biological role for PKCbetaIotaIota in NF-kappaB-mediated CCL11 transcription by p/CAF activation and histone H4 acetylation.
ISSN:1550-6606