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

Abstract

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

Protein Kinase C-δ (PKCδ) Regulates Proinflammatory Chemokine Expression through Cytosolic Interaction with the NF-κB Subunit p65 in Vascular Smooth Muscle Cells

“…In HEK293 and U2OS cells, PKC␦ forms complexes with p65 in the nucleus following TNF␣ exposure. The PKC␦-p65 complex is believed to occupy NF-B target gene promoters and orchestrate RelA/p65 transactivation (14). Our study revealed another mechanism that involves a cytosol-specific PKC␦-p65 interaction that is independent of the IB pathway.…”

“…Consistent with this hypothesis, overexpression of the catalytic fragment in the absence of an apoptotic stimulus was sufficient to induce apoptosis in a variety of cell types (10). In contrast, several lines of studies showed a pivotal role for PKC␦ in antiapoptotic function in response to cytokines including tumor necrosis factor-␣ (TNF␣) (14). Silencing PKC␦ expression by siRNA resulted in inhibition of TNF-mediated extracellular signal-regulated kinase 1/2 activation (15).…”

Trimeric G protein-CARMA1 axis links smoothened, the hedgehog receptor transducer, to NF-κB activation in diffuse large B-cell lymphoma

“…Previous studies have showed that activation of different PKC isoforms results in NF-kB activation. [41][42][43] It has been reported that, in embryonic mouse stem cells, Shh enhances the translocation of PKCa, d, and z isoforms from the cytosol to the cytoplasmic membrane supporting Hh-induced activation of these PKC isoforms. 31 Earlier studies have found that CARMA3 and TRAF6 are required for GPCR-induced NF-kB activation in Mef cells.…”

Phorbol Ester-Induced Human Cytomegalovirus Major Immediate-Early (MIE) Enhancer Activation through PKC-Delta, CREB, and NF-κB Desilences MIE Gene Expression in Quiescently Infected Human Pluripotent NTera2 Cells

“…The activation of PKC-delta by other stimuli (e.g., thrombin, bryostatin, and tumor necrosis factor alpha [TNF-␣]) is also sufficient to drive the NF-Bdependent transcription of cellular genes (ICAM-1, interleukin-8 , and RelA/p65) in human endothelial, epithelial, and osteosarcoma cells (5,32,43). In HFF, smooth muscle cells, endothelial cells, and monocytes, HCMV infection rapidly results in NF-B translocation to the cell nucleus and NF-B binding to the B site in DNA, regardless of the HCMV strain tested.…”