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Ubiquitin ligases define the substrate specificity of protein ubiquitination and subsequent proteosomal degradation. The catalytic sequence was first characterized in the C terminus of E6-associated protein (E6AP) and referred to as the HECT (homologous to E6AP C terminus) domain. The human homologue of the regulator of cell proliferation hyperplastic discs in Drosophila, designated hHYD, is a HECT-domain ubiquitin ligase. Here we show that hHYD provides a ubiquitin system for a cellular response to DNA damage. A yeast twohybrid screen showed that DNA topoisomerase II␤-binding protein 1 (TopBP1) interacted with hHYD. Endogenous hHYD bound the BRCA1 C-terminus domains of TopBP1 that are highlighted in DNA damage checkpoint proteins and cell cycle regulators. Using an in vitro reconstitution, specific E2 (ubiquitin-conjugating) enzymes (human UbcH4, UbcH5B, and UbcH5C) transferred ubiquitin molecules to hHYD, leading to the ubiquitination of TopBP1. TopBP1 was usually ubiquitinated and degraded by the proteosome, whereas X-irradiation diminished the ubiquitination of TopBP1 probably via the phosphorylation, resulting in the stable colocalization of up-regulated TopBP1 with ␥-H2AX nuclear foci in DNA breaks. These results demonstrated that hHYD coordinated TopBP1 in the DNA damage response.The ubiquitin-proteosome proteolytic system is involved in a variety of fundamental cell regulations including gene expression, stress response, DNA repair, and cell cycles (1-6). Ubiquitination includes a cascade of three classes of enzymes, the ubiquitin-activating enzyme E1, 1 the ubiquitin-conjugating enzyme Ubc or E2, and the ubiquitin ligase E3. After activation of a ubiquitin by E1, E2 and E3 cooperate to catalyze the formation of a multiubiquitin chain on a protein substrate. The E3 enzymes or the protein complexes with a ligase activity are believed to target the substrate for selective ubiquitination and a subsequent turnover by a large protease complex, the 26 S proteosome. There are two distinct groups of human ubiquitin ligases, the HECT domain E3 enzymes, including E6-associated protein (E6AP) and NEDD4, and the RING finger E3 enzymes, including SCF (Skp1-cullin-F box), VBC (VHL-Elongin B-Elongin C), APC (anaphase-promoting complex) and other single RING finger proteins such as c-Cbl and MDM2 (7). The HECT sequence of ϳ200 amino acids is highly conserved in the C-terminal catalytic domain of family members from yeast to mammals. The HECT-domain protein forms a thiol ester bond with a ubiquitin at the active cysteine residue and transfers the ubiquitin directly to the substrate (8 -10), whereas RING finger proteins form complexes containing an E2 enzyme, which facilitate ubiquitination of the substrate. However, the overall mechanisms by which these ubiquitin ligases recognize the target proteins remain to be elucidated.In the present study, we focused on characterizing the human HECT-domain protein, a counterpart of the regulator of cell proliferation and the putative tumor suppressor hyperplastic discs in Drosophil...

Supplementation with BB536 was well tolerated and reduced UCDAI scores, EI and Mayo subscores after 8 weeks in Japanese patients with mild to moderately active UC.

ABSTRACT:This review focuses on the world's first process succeeded in development and industrialization by Asahi Kasei Corp. for producing an aromatic polycarbonate (PC) using CO 2 as starting material.

This paper focuses on the world's first nonphosgene process using CO 2 as starting material succeeded in development and industrialization by Asahi Kasei Corp. The Asahi Kasei Process enables high-yield production of high-quality PC having excellent properties and high-purity monoethylene glycol (MEG), starting from ethylene oxide (EO), by-produced CO 2 and bisphenol-A without waste and waste water. The innovative reactive distillation technologies in the monomer production and the innovative gravity-utilized, non-agitation polymerization reactor in the melt polymerization, led the new process to success. The monomer process consists of 3 production steps, ethylene carbonate (EC) from CO 2 and EO, dimethyl carbonate (DMC) and MEG from EC and MeOH, and diphenyl carbonate (DPC) and MeOH from DMC and PhOH. All intermediates are recycled. The new type polymerization reactor perfectly overcomes the difficulty based on the extremely high viscosity in the melt polymerization of DPC with Bis-A. The by-produced PhOH is recycled to the monomer process. The reduction of CO 2 emissions (0.173t/ PC 1t) is also achieved, because CO 2 used as raw material is utilized as the main chain components of the products. Four commercial plants (Taiwan: 150,000 t/y, Korea: 2 plants of 65,000 t/y, Russia: 65,000 t/y) using the Asahi Kasei Process are now successfully operating, and the plant of 260,000 t/y in Saudi Arabia will start in 2010.

The aryl hydrocarbon receptor nuclear transporter (ARNT) is a member of the basic helix-loop-helix/PAS (Per-ARNT-Sim) family of transcription factors, which are important for cell regulation in response to environmental conditions. ARNT is an indispensable partner of the aryl hydrocarbon receptor (AHR) or hypoxia-inducible factor-1␣. This protein is also able to form homodimers such as ARNT/ARNT. However, the molecular mechanism that regulates the transcriptional activity of ARNT remains to be elucidated. Here, we report that ARNT is modified by SUMO-1 chiefly at Lys 245 within the PAS domain of this protein, both in vivo and in vitro. Substitution of the target lysine with alanine enhanced the transcriptional potential of ARNT per se. Furthermore, green fluorescent protein-fused ARNT tended to form nuclear foci in ϳ20% of the transfected cells, and the foci partly colocalized with PML nuclear bodies. PML, one of the well known substrates for sumoylation, was found to augment the transcriptional activities of ARNT. ARNT bound AHR or PML, whereas the sumoylated form of ARNT associated with AHR, but not with PML, resulting in a reduced effect of PML on transactivation by ARNT. Our data suggest that the sumoylation of ARNT modulates its transcriptional role through affecting the ability of ARNT to interact with cooperative molecules such as PML. This exemplifies a crucial role of protein sumoylation in modulating protein-protein interactions.

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