title: Nuclear Translocation of p65 is Controlled by Sec6 via the Degradation of IκBα.
abstract: Nuclear factor-κB (NF-κB) is an inducible transcription factor that mediates immune and inflammatory responses. NF-κB pathways are also involved in cell adhesion, differentiation, proliferation, autophagy, senescence, and protection against apoptosis. The deregulation of NF-κB activity is found in a number of disease states, including cancer, arthritis, chronic inflammation, asthma, neurodegenerative diseases, and heart disease. The 90 kDa ribosomal S6 kinase (p90RSK) family, which is serine/threonine kinases, is phosphorylated by extracellular signal-regulated kinase1/2 (ERK1/2) and is related to NF-κB pathways. Our previous studies revealed that Sec6, a component of the exocyst complex, plays specific roles in cell-cell adhesion and cell cycle arrest. However, the mechanism by which Sec6 regulates the NF-κB signaling pathway is unknown. We demonstrated that Sec6 knockdown inhibited the degradation of IκBα and delayed the nucleus-cytoplasm translocation of p65 in HeLa cells transfected with Sec6 siRNAs after treatment with tumor necrosis factor alpha (TNF-α). Furthermore, the binding of p65 and cAMP response element binding protein (CREB) binding protein (CBP) or p300 decreased and NF-κB related genes which were inhibitors of NF-κB alpha (IκBα), A20, B cell lymphoma protein 2 (Bcl-2), and monocyte chemoattractant protein-1 (MCP-1) were low in cells transfected with Sec6 siRNAs in response to TNF-α stimulation. Sec6 knockdown decreased the expression of p90RSKs and the phosphorylation of ERK or p90RSK1 at Ser380 or IκBα at Ser32. The present study suggests that Sec6 regulates NF-κB transcriptional activity via the control of the phosphorylation of IκBα, p90RSK1, and ERK.
authors.affiliation: Department of Anatomy and Cell Biology, School of Medicine, Yamagata University, 2-2-2 Iidanishi, Yamagata, Japan.|Department of Dentistry, Oral and Maxillofacial Surgery, Plastic and Reconstructive Surgery, School of Medicine, Yamagata University, 2-2-2 Iidanishi, Yamagata, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Tanaka
authors.affiliation: Department of Dentistry, Oral and Maxillofacial Surgery, Plastic and Reconstructive Surgery, School of Medicine, Yamagata University, 2-2-2 Iidanishi, Yamagata, Japan.
authors.forename: Mitsuyoshi
authors.initials: M
authors.lastname: Iino
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000502:physiology; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D020672:I-kappa B Proteins / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D010766:Phosphorylation; D021381:Protein Transport / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D051996:Transcription Factor RelA / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D033921:Vesicular Transport Proteins / Q000378:metabolism*
chemical_list: C490685:EXOC3 protein, human; D020672:I-kappa B Proteins; C000606204:NFKBIA protein, human; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D033921:Vesicular Transport Proteins; D000072000:NF-KappaB Inhibitor alpha; D051550:I-kappa B Kinase