Inhibitors of protein kinase C (PKC) prevent activated transcription: role of events downstream of NF-kappaB DNA binding

Catley, Matthew C., Cambridge, Lisa M., Nasuhara, Yasuyuki, Ito, Kazuhiro, Chivers, Joanna E, Beaton, Andrew, Holden, Neil S., Bergmann, Martin W., Barnes, Peter J. and Newton, Robert (2004) Inhibitors of protein kinase C (PKC) prevent activated transcription: role of events downstream of NF-kappaB DNA binding. Journal of Biological Chemistry, 279 (18). pp. 18457-18466. ISSN 0021-9258

Full content URL: http://dx.doi.org/10.1074/jbc.M400765200

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Item Type:Article
Item Status:Live Archive

Abstract

In pulmonary A549 cells, the protein kinase C (PKC) inhibitor, Ro 31-8220, and the phosphotidylcholine-specific phospholipase C inhibitor, D609, prevent NF-kappaB-dependent transcription, yet NF-kappaB DNA binding is unaffected (Bergmann, M., Hart, L., Lindsay, M., Barnes, P. J., and Newton, R. (1998) J. Biol. Chem. 273, 6607-6610). We now show that this effect also occurs in BEAS-2B bronchial epithelial cells as well as with other PKC inhibitors (Gö 6976, GF109203X, and calphostin C) in A549 cells. Similarly, phorbol ester, a diacylglycerol mimetic, activates NF-kappaB-dependent transcription and potentiates tumor necrosis factor alpha (TNFalpha)-induced NF-kappaB-dependent transcription, yet unlike TNFalpha, poorly activates IkappaB kinase (IKK) activity, IkappaBalpha degradation, or NF-kappaB DNA binding in both A549 and BEAS-2B cells. As phorbol ester-induced NF-kappaB-dependent transcription was relatively insensitive to the proteasome inhibitor, MG-132, PKC may affect NF-kappaB-dependent transcription via mechanisms other than the core IKK-IkappaB pathway. This is supported by Gal4 one hybrid analysis of p65/RelA transactivation, which was potentiated by TNFalpha and phorbol ester and was inhibited by Ro 31-8220 and D609. Additionally, a number of PKC isoforms, particularly the novel isoform PKCepsilon, induced p65/RelA transactivation. Phosphorylation of p65/RelA and cAMP-responsive element-binding protein (CREB)-binding protein (CBP) was increased by TNFalpha treatment and, in the case of CBP, was prevented by Ro 31-8220 or D609. However, p65/RelA-CBP interactions were unaffected by either compound. As this effect was not limited to NF-kappaB, but was a more general feature of inducible gene transcription, we suggest PKC isoforms may provide a point of intervention in diseases such as inflammation, or cancer, where activated gene expression is prominent.

Keywords:Protein kinase
Subjects:C Biological Sciences > C720 Biological Chemistry
Divisions:College of Science > School of Life Sciences
ID Code:15131
Deposited On:08 Jun 2015 16:24

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