Protein Kinase Cδ Activates RelA/p65 and Nuclear Factor-κB Signaling in Response to Tumor Necrosis Factor-α

Nuclear factor-kappa B (NF-kappa B) is tightly modulated by I kappa B kinases and I kappa B alpha in the cytoplasm. On stimulation, NF-kappa B translocates into the nucleus to initiate transcription; however, regulation of its transcriptional activity remains obscure. Here, we show that protein kinase C (PKC) delta controls the main subunit of NF-kappa B, RelA/p65. On exposure to tumor necrosis factor-alpha (TNF-alpha), the expression of RelA/p65 target genes such as I kappa B alpha, RelB, and p100/p52 is upregulated in a PKC delta-dependent manner. The results also show that PKC delta is targeted to the nucleus and forms a complex with RelA/p65 following TNF-alpha exposure. Importantly, kinase activity of PKC delta is required for RelA/p65 transactivation. In concert with these results, PKC delta activates RelA/p65 for its occupancy to target-gene promoters, including I kappa B alpha and p100/p52. Moreover, functional analyses show that inhibition of PKC delta is associated with substantial attenuation of NF-kappa B activity in response to TNF-alpha. These findings provide evidence that PKC delta orchestrates RelA/p65 transactivation, a requisite for NF-kappa B signaling pathway in the nucleus. [Cancer Res 2009;69(14):5927-35]