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  • Title: Inhibitors of protein kinase C (PKC) prevent activated transcription: role of events downstream of NF-kappaB DNA binding.
    Author: Catley MC, Cambridge LM, Nasuhara Y, Ito K, Chivers JE, Beaton A, Holden NS, Bergmann MW, Barnes PJ, Newton R.
    Journal: J Biol Chem; 2004 Apr 30; 279(18):18457-66. PubMed ID: 14976190.
    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.
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