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Protein Kinase C Activates RelA/p65 and Nuclear Factor-B Signaling in Response to Tumor Necrosis Factor-

Department of Molecular Genetics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan

Requests for reprints: Kiyotsugu Yoshida, Department of Molecular Genetics, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan. Phone: 81-3-5803-5826; Fax: 81-3-5803-0242; E-mail: yos.mgen{at}mri.tmd.ac.jp.

Key Words: PKC • RelA/p65 • NF-B • transactivation • TNF-

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