The fifth component of the COP9 signalosome complex, Jab1/CSN5, directly binds to and induces specific downregulation of the cyclin-dependent kinase inhibitor p27 (p27 Kip1 ). Nuclear-cytoplasmic translocation plays an important role because leptomycin B (LMB), a chemical inhibitor of CRM1-dependent nuclear export, prevents p27 degradation mediated by Jab1/CSN5. Here we show that Jab1/CSN5 functions as an adaptor between p27 and CRM1 to induce nuclear export and subsequent degradation. Jab1/CSN5, but not p27, contains a typical leucinerich nuclear export signal (NES) sequence conserved among different species, through which CRM1 bound to Jab1/CSN5 in an LMB-sensitive manner. Alteration of conserved leucine residues to alanine within Jab1/CSN5-NES abolished the interaction with CRM1 in vitro and impaired LMB-sensitive nuclear export and the ability to induce p27 breakdown in cultured cells. A Jab1/CSN5 truncation mutant lacking NES reversed p27 down-regulation induced by the full-length Jab1/CSN5, indicating that this mutant functions as a dominant negative (DNJab1). Introduction of DN-Jab1 into proliferating fibroblasts increased the level of p27 protein, thereby inducing growth arrest of the cells. Random mutagenesis analysis revealed that specific aspartic acid, leucine, and asparagine residues contained in the Jab1/CSN5-binding domain of p27 were required for interaction with Jab1/CSN5 and for down-regulation of p27. Glycerol gradient and cell fractionation experiments showed that at least two different forms of Jab1/CSN5-containing complexes existed within the cell. One is the conventional 450-kDa COP9 signalosome (CSN) complex located in the nucleus, and the other is much smaller (around 100-kDa), containing only a subset of CSN components (CSN4 -8 but not CSN1-3), and mainly located in the cytoplasm. Treatment of cells with LMB greatly reduced the level of the smaller complex, suggesting that it originated from the CSN complex by nuclear export. Besides Jab1/CSN5, CSN3, ؊6, ؊7, and ؊8 were capable of inducing p27 down-regulation, when ectopically expressed. These results indicate that cytoplasmic shuttling regulated by Jab1/CSN5 and other CSN components may be a new pathway to control the intracellular abundance of the key cell cycle regulator.

The design progress in a compact low aspect ratio (low A) DEMO reactor, ‘SlimCS’, and its design issues are reported. The design study focused mainly on the torus configuration including the blanket, divertor, materials and maintenance scheme. For continuity with the Japanese ITER-TBM, the blanket is based on a water-cooled solid breeder blanket. For vertical stability of the elongated plasma and high beta access, the blanket is segmented into replaceable and permanent blankets and a sector-wide conducting shell is arranged inbetween these blankets. A numerical calculation indicates that fuel self-sufficiency can be satisfied when the blanket interior is ideally fabricated. An allowable heat load to the divertor plate should be 8 MW m−2 or lower, which can be a critical constraint for determining a handling power of DEMO.

The ubiquitously expressed 14-3-3 proteins regulate many pathways involved in transformation. Previously, we found that 14-3-3ζ overexpression increased Akt phosphorylation in human mammary epithelial cells. Here, we investigated the clinical relevance and molecular mechanism of 14-3-3ζ overexpression-mediated Akt phosphorylation and the potential impact on breast cancer progression. We found that 14-3-3ζ overexpression was significantly (P = 0.005) associated with increased Akt phosphorylation in human breast tumors. Additionally, 14-3-3ζ overexpression combined with strong Akt phosphorylation was significantly (P=0.01) associated with increased cancer recurrence in patients. In contrast, knockdown of 14-3-3ζ expression by siRNA in cancer cell lines and tumor xenografts reduced Akt phosphorylation. Furthermore, 14-3-3ζ enhanced Akt phosphorylation through activation of PI3K. Mechanistically, 14-3-3ζ bound to the p85 regulatory subunit of PI3K and increased PI3K translocation to the cell membrane. A single 14-3-3 binding motif encompassing serine 83 on p85 is largely responsible for 14-3-3ζ-mediated p85 binding and PI3K/Akt activation. Mutation of serine 83 to alanine on p85 inhibited 14-3-3ζ binding to the p85 subunit of PI3K, reduced PI3K membrane localization and activation, impeded anchorage independent growth and enhanced stress induced apoptosis. These findings revealed a novel mechanism by which 14-3-3ζ overexpression activates PI3K, a key node in the mitogenic signaling network known to promote malignancies in many cell types.

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The compact reversed shear tokamak CREST is a cost competitive reactor concept based on a reversed shear high β plasma and water cooled ferritic steel components. The moderate aspect ratio A = 3.4 and the elongation κ = 2.0 of CREST are very similar to the case of the ITER advanced mode plasma. Presentation of such a concept based on the ITER project should be worth while for formulating a fusion development strategy. The achievement of a competitive cost of electricity (COE) is the first priority for electric power industries. High β and high thermal efficiency are the most effective parameters for achieving a competitive COE. In order to achieve a high efficiency power plant, a superheated steam cycle has been adopted which permits a high thermal efficiency (η = 41%). Current profile control and high speed plasma rotation by neutral beam current drive stabilize the ideal MHD activity up to the Troyon coefficient βN = 5.5. A cost assessment has shown that CREST could generate about 1.16 GW(e) electric power at a competitive cost.