Protein kinase Cdelta activates RelA/p65 and nuclear factor-kappaB signaling in response to tumor necrosis factor-alpha.
Nuclear factor-kappaB (NF-kappaB) is tightly modulated by IkappaB kinases and IkappaBalpha in the cytoplasm. On stimulation, NF-kappaB 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-kappaB, RelA/p65. On exposure to tumor necrosis factor-alpha (TNF-alpha), the expression of RelA/p65 target genes such as IkappaBalpha, RelB, and p100/p52 is up-regulated in a PKCdelta-dependent manner. The results also show that PKCdelta is targeted to the nucleus and forms a complex with RelA/p65 following TNF-alpha exposure. Importantly, kinase activity of PKCdelta is required for RelA/p65 transactivation. In concert with these results, PKCdelta activates RelA/p65 for its occupancy to target-gene promoters, including IkappaBalpha and p100/p52. Moreover, functional analyses show that inhibition of PKCdelta is associated with substantial attenuation of NF-kappaB activity in response to TNF-alpha. These findings provide evidence that PKCdelta orchestrates RelA/p65 transactivation, a requisite for NF-kappaB signaling pathway in the nucleus.
Lu
Zheng-Guang
ZG
Department of Molecular Genetics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
Liu
Hanshao
H
Yamaguchi
Tomoko
T
Miki
Yoshio
Y
Yoshida
Kiyotsugu
K
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D024202:Electrophoretic Mobility Shift Assay; D006801:Humans; D015151:Immunoblotting; D020287:In Situ Nick-End Labeling; D015850:Interleukin-6 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D051745:Protein Kinase C-delta / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects; D034741:RNA, Small Interfering / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D051996:Transcription Factor RelA / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D015850:Interleukin-6; D016328:NF-kappa B; C498143:RELA protein, human; D034741:RNA, Small Interfering; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D051745:Protein Kinase C-delta