title: Downregulation of diacylglycerol kinase ζ enhances activation of cytokine-induced NF-κB signaling pathway.
abstract: The transcription factor NF-κB family serves as a key component of many pathophysiological events such as innate and adaptive immune response, inflammation, apoptosis, and oncogenesis. Various cell signals trigger activation of the regulatory mechanisms of NF-κB, resulting in its nuclear translocation and transcriptional initiation. The diacylglycerol kinase (DGK) family, a lipid second messenger-metabolizing enzyme in phosphoinositide signaling, is shown to regulate widely various cellular processes. Results of recent studies suggest that one family member, DGKζ, is closely involved in immune and inflammatory responses. Nevertheless, little is known about the regulatory mechanism of DGKζ on NF-κB pathway in cytokine-induced inflammatory signaling. This study shows that siRNA-mediated DGKζ knockdown in HeLa cells facilitates degradation of IκB, followed by nuclear translocation of NF-κB p65 subunit. In addition, DGKζ-deficient MEFs show upregulation of p65 subunit phosphorylation at Serine 468 and 536 and its interaction with CBP transcriptional coactivator upon TNF-α stimulation. These modifications of p65 subunit might engender enhanced NF-κB transcriptional reporter assay of DGKζ knockdown cells. These findings provide further insight into the regulatory mechanisms of cytokine-induced NF-κB activation.
authors.affiliation: Department of Anatomy and Cell Biology, Yamagata University School of Medicine, Yamagata 990-9585, Japan; Department of Dentistry, Oral and Maxillofacial Plastic and Reconstructive Surgery, Yamagata University School of Medicine, Yamagata 990-9585, Japan.
authors.forename: Rieko
authors.initials: R
authors.lastname: Tsuchiya
authors.affiliation: Department of Anatomy and Cell Biology, Yamagata University School of Medicine, Yamagata 990-9585, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Tanaka
authors.affiliation: Department of Anatomy and Cell Biology, Yamagata University School of Medicine, Yamagata 990-9585, Japan.
authors.forename: Yasukazu
authors.initials: Y
authors.lastname: Hozumi
authors.affiliation: Department of Anatomy and Cell Biology, Yamagata University School of Medicine, Yamagata 990-9585, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Nakano
authors.affiliation: Department of Anatomy and Cell Biology, Yamagata University School of Medicine, Yamagata 990-9585, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Okada
authors.affiliation: Huntsman Cancer Institute, Department of Oncological Sciences, University of Utah, Salt Lake City, UT 84112, USA.
authors.forename: Matthew K
authors.initials: MK
authors.lastname: Topham
authors.affiliation: Department of Dentistry, Oral and Maxillofacial Plastic and Reconstructive Surgery, Yamagata University School of Medicine, Yamagata 990-9585, Japan.
authors.forename: Mitsuyoshi
authors.initials: M
authors.lastname: Iino
authors.affiliation: Department of Anatomy and Cell Biology, Yamagata University School of Medicine, Yamagata 990-9585, Japan. Electronic address: kgoto@med.id.yamagata-u.ac.jp.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Goto
mesh_terms: D000818:Animals; D050882:CREB-Binding Protein / Q000378:metabolism; D016207:Cytokines / Q000494:pharmacology*; D019852:Diacylglycerol Kinase / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects*; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology; D055785:Gene Knockdown Techniques; D006367:HeLa Cells; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects; D034622:RNA Interference / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D016207:Cytokines; D020672:I-kappa B Proteins; D016328:NF-kappa B; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D050882:CREB-Binding Protein; C526463:DGKZ protein, human; D019852:Diacylglycerol Kinase; C512480:diacylglycerol kinase zeta, mouse
keywords: CBP; Diacylglycerol kinase ζ; Inflammation; NF-κB; Nuclear translocation; TNF-α