NGFR
In pulmonary
A549 cells, the protein kinase C (PKC) inhibitor, Ro 31-8220, and the
phosphotidylcholine-specific phospholipase C (PC-PLC) inhibitor, D609, prevent
NF- B-dependent transcription, yet NF- B DNA binding is unaffected (Bergmann et
al. 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 (G 6976, GF109203X and calphostin C) in A549 cells. Similarly,
phorbol ester, a diacyl glycerol mimetic, activates NF- B-dependent
transcription and potentiates TNFa-induced NF- B-dependent transcription, yet
unlike TNFa, poorly activates I B kinase (IKK) activity, I Ba degradation or
NF- B DNA binding in both A549 and BEAS-2B cells. As phorbol ester-induced NF-
B-dependent transcription was relatively insensitive to the proteasome
inhibitor, MG-132, PKC may affect NF- B-dependent transcription via mechanisms
other than the core IKK-I B pathway. This is supported by Gal4 one hybrid
analysis of p65/RelA transactivation, which was potentiated by TNFa and phorbol
ester and was inhibited by Ro 31-8220 and D609. Additionally, a number of PKC
isoforms, particularly the novel isoform PKCe, induced p65/RelA
transactivation. Phosphorylation of p65/RelA and CREB binding protein (CBP) was
increased by TNFa 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- B, 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.
PMID: 14976190 [PubMed - as supplied by publisher]