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Phorbol ester-stimulated NF-kappa B-dependent transcription : Roles for isoforms of novel protein kinase C
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Holden, Neil S., Squires, Paul E., Kaur, Manminder, Bland, R. (Rosemary), Jones, Carol E. and Newton, R. (Robert) (2008) Phorbol ester-stimulated NF-kappa B-dependent transcription : Roles for isoforms of novel protein kinase C. Cellular Signalling, Volume 20 (Number 7). pp. 1338-1348. doi:10.1016/j.cellsig.2008.03.001 ISSN 0898-6568.
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Official URL: http://dx.doi.org/10.1016/j.cellsig.2008.03.001
Abstract
Since protein kinase C (PKC) isoforms are variously implicated in the activation of NF-kappa B, we have investigated the role of PKC in the activation of NF-kappa B-dependent transcription by the diacyl glycerol (DAG) mimetic, phorbol 12-myristate 13-acetate (PMA), and by tumour necrosis factor (TNF) a in pulmonary A549 cells. The PKC selective inhibitors, Ro31-8220, Go6976, GF109203X and Go6983, revealed no effect on TNF alpha-induced NF kappa B DNA binding and a similar lack of effect on serine 32/36 phosphorylated I kappa B alpha and the loss of total I kappa B alpha, indicates that activation of the core IKK-I kappa B alpha-NF-kappa B cascade by TNF alpha does not involve PKC. In contrast, differential sensitivity of an NF-kappa B-dependent reporter to Ro31-8220, Go6976, GF109203X and Go6983 (EC50S 0.46 mu M, 0.34 mu M, > 10 mu M and > 10 mu M respectively) suggests a role for protein kinase D in transcriptional activation by TNF alpha. Compared with TNFa, PMA weakly induces NF-kappa B DNA binding and this effect was not associated with serine 32/36 phosphorylation of I kappa B alpha. However, PMA-stimulated NF-kappa B DNA binding was inhibited by Ro31-8220 (10 mu M), GF109203X (10 mu M) and Go6983 (10 mu M), but not by Go6976 (10 mu M), suggesting a role for novel PKCisoforms. Furthermore,a lack of positive effect of calcium mobilising agents on both NF-kappa B DNA binding and on transcriptional activation argues against major roles for classical PKCs. This, combined with the ability of both GF109203X and Go6983 to prevent enhancement of TNF alpha-induced NF-kappa B-dependent transcription by PMA, further indicates a role for novel PKCs in NF-kappa B transactivation. Finally, siRNA-mediated knockdown of PKC delta and epsilon, expression did not affect TNFa-induced NF-kappa B-dependent transcription. However, knockdown of PKC delta expression significantly inhibited PMA-stimulated luciferase activity, whereas knockdown of PKC epsilon was without effect. Furthermore, combined knockdown of PKC delta and E revealed an increased inhibitory effect on PMA-stimulated NF-kappa B-dependent transcription suggesting that PMA-induced NF-kappa B-dependent transcription is driven by novel PKC isoforms, particularly PKC delta and epsilon. (c) 2008 Elsevier Inc. All rights reserved.
Item Type: | Journal Article | ||||
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Subjects: | Q Science > QH Natural history > QH426 Genetics Q Science > QP Physiology |
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Divisions: | Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- ) > Biological Sciences ( -2010) | ||||
Library of Congress Subject Headings (LCSH): | NF-kappa B (DNA-binding protein), Protein kinase C, Transcription factors, Pulmonary endothelium, Epithelium, Gene expression, Phorbol esters | ||||
Journal or Publication Title: | Cellular Signalling | ||||
Publisher: | Elsevier | ||||
ISSN: | 0898-6568 | ||||
Official Date: | July 2008 | ||||
Dates: |
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Volume: | Volume 20 | ||||
Number: | Number 7 | ||||
Number of Pages: | 11 | ||||
Page Range: | pp. 1338-1348 | ||||
DOI: | 10.1016/j.cellsig.2008.03.001 | ||||
Status: | Peer Reviewed | ||||
Publication Status: | Published | ||||
Access rights to Published version: | Restricted or Subscription Access | ||||
Funder: | Novartis Pharmaceuticals UK, Canadian Institutes of Health Research (CIHR), Alberta Heritage Foundation for Medical Research (AHFMR) |
Data sourced from Thomson Reuters' Web of Knowledge
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