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991.
Solution structure of the SEA domain from the murine homologue of ovarian cancer antigen CA125 (MUC16) 总被引:7,自引:0,他引:7
Maeda T Inoue M Koshiba S Yabuki T Aoki M Nunokawa E Seki E Matsuda T Motoda Y Kobayashi A Hiroyasu F Shirouzu M Terada T Hayami N Ishizuka Y Shinya N Tatsuguchi A Yoshida M Hirota H Matsuo Y Tani K Arakawa T Carninci P Kawai J Hayashizaki Y Kigawa T Yokoyama S 《The Journal of biological chemistry》2004,279(13):13174-13182
Human CA125, encoded by the MUC16 gene, is an ovarian cancer antigen widely used for a serum assay. Its extracellular region consists of tandem repeats of SEA domains. In this study we determined the three-dimensional structure of the SEA domain from the murine MUC16 homologue using multidimensional NMR spectroscopy. The domain forms a unique alpha/beta sandwich fold composed of two alpha helices and four antiparallel beta strands and has a characteristic turn named the TY-turn between alpha1 and alpha2. The internal mobility of the main chain is low throughout the domain. The residues that form the hydrophobic core and the TY-turn are fully conserved in all SEA domain sequences, indicating that the fold is common in the family. Interestingly, no other residues are conserved throughout the family. Thus, the sequence alignment of the SEA domain family was refined on the basis of the three-dimensional structure, which allowed us to classify the SEA domains into several subfamilies. The residues on the surface differ between these subfamilies, suggesting that each subfamily has a different function. In the MUC16 SEA domains, the conserved surface residues, Asn-10, Thr-12, Arg-63, Asp-75, Asp-112, Ser-115, and Phe-117, are clustered on the beta sheet surface, which may be functionally important. The putative epitope (residues 58-77) for anti-MUC16 antibodies is located around the beta2 and beta3 strands. On the other hand the tissue tumor marker MUC1 has a SEA domain belonging to another subfamily, and its GSVVV motif for proteolytic cleavage is located in the short loop connecting beta2 and beta3. 相似文献
992.
993.
Arai M Sato H Kobayashi H Suganuma M Kawabe T Tomoda H Omura S 《Biochemical and biophysical research communications》2004,317(3):817-822
Human T-cell leukemia-derived Jurkat cells are known to be defective in the G1 checkpoint. DNA-damaging agent bleomycin arrests the cell cycle at G2 phase of Jurkat cells, and microtubule-acting colchicine arrests it at the M phase. Simaomicin alpha, an actinomycete metabolite, itself showed no effect on the cell cycle status of Jurkat cells at least up to 6.0 nM. However, the compound (0.6-6.0 nM) was found to abrogate the bleomycin-induced G2 arrest, yielding a drastic decrease in cells at the G2 phase and increase in cells at the subG1 and G1 phases. On the other hand, the compound did not show any effect on the colchicine-induced M phase arrest in Jurkat cells. Furthermore, the compound showed almost no effect on the cell cycle status of the bleomycin-treated or -untreated normal cell line HUVEC. These data suggested that simaomicin alpha disrupts the cell cycle G2 checkpoint of cancer cells selectively, leading to sensitization of cancer cells to anti-cancer reagents. 相似文献
994.
995.
Apelin is a novel angiogenic factor in retinal endothelial cells 总被引:29,自引:0,他引:29
996.
Astecker N Bobrovnikova EA Omdahl JL Gennaro L Vouros P Schuster I Uskokovic MR Ishizuka S Wang G Reddy GS 《Archives of biochemistry and biophysics》2004,431(2):261-270
Recently, 25-hydroxyvitamin D3-24-hydroxylase (CYP24A1) has been shown to catalyze not only hydroxylation at C-24 but also hydroxylations at C-23 and C-26 of the secosteroid hormone 1alpha, 25-dihydroxyvitamin D3 (1alpha,25(OH)2D3). It remains to be determined whether CYP24A1 has the ability to hydroxylate vitamin D3 compounds at C-25. 1alpha,24(R)-dihydroxyvitamin D3 (1alpha,24(R)(OH)2D3) is a non-25-hydroxylated synthetic vitamin D3 analog that is presently being used as an antipsoriatic drug. In the present study, we investigated the metabolism of 1alpha,24(R)(OH)2D3 in human keratinocytes in order to examine the ability of CYP24A1 to hydroxylate 1alpha,24(R)(OH)2D3 at C-25. The results indicated that keratinocytes metabolize 1alpha,24(R)(OH)2D3 into several previously known both 25-hydroxylated and non-25-hydroxylated metabolites along with two new metabolites, namely 1alpha,23,24(OH)3D3 and 1alpha,24(OH)2-23-oxo-D3. Production of the metabolites including the 25-hydroxylated ones was detectable only when CYP24A1 activity was induced in keratinocytes 1alpha,25(OH)2D3. This finding provided indirect evidence to indicate that CYP24A1 catalyzes C-25 hydroxylation of 1alpha,24(R)(OH)2D3. The final proof for this finding was obtained through our metabolism studies using highly purified recombinant rat CYP24A1 in a reconstituted system. Incubation of this system with 1alpha,24(R)(OH)2D3 resulted in the production of both 25-hydroxylated and non-25-hydroxylated metabolites. Thus, in our present study, we identified CYP24A1 as the main enzyme responsible for the metabolism of 1alpha,24(R)(OH)2D3 in human keratinocytes, and provided unequivocal evidence to indicate that the multicatalytic enzyme CYP24A1 has the ability to hydroxylate 1alpha,24(R)(OH)2D3 at C-25. 相似文献
997.
Study of drug effects of calcium channel blockers on retinal degeneration of rd mouse 总被引:9,自引:0,他引:9
Takano Y Ohguro H Dezawa M Ishikawa H Yamazaki H Ohguro I Mamiya K Metoki T Ishikawa F Nakazawa M 《Biochemical and biophysical research communications》2004,313(4):1015-1022
In the present study, we studied drug effects of Ca(2+) antagonists on the retinal degeneration of rd mouse to evaluate their efficacy. Several kinds of Ca(2+) antagonists, diltiazem, nicardipine, nilvadipine or nifedipine were administrated intraperitoneally and thereafter retinal morphology and functions were analyzed. In addition, we performed DNA microarray analysis both in nilvadipine treated and control retinas to understand their drug effects at molecular levels. We found that nilvadipine caused significant preservation of retinal thickness in rd mouse during the initial stage of the retinal degeneration, and nicardipine showed also significant but lesser preservation than nilvadipine. However, we recognized no preservation effects of diltiazem and nifedipine. In the total 3774 genes, the expressions of 27 genes were altered upon administration of nilvadipine, including several genes related to the apoptotic pathway, neuro-survival factor, Ca(2+) metabolisms, and other mechanisms. It is suggested that some types of Ca(2+) channel blockers, such as nilvadipine and nicardipine, are able to preserve photoreceptor cells in rd mouse and can potentially be used to treat some RP patients. 相似文献
998.
Wang Y Suzuki H Yokoo T Tada-Iida K Kihara R Miura M Watanabe K Sone H Shimano H Toyoshima H Yamada N 《Biochemical and biophysical research communications》2004,324(3):1053-1058
Rho family GTPases regulate multiple cellular processes through their downstream effectors, where their activities are stimulated by the guanine nucleotide exchange factors. Here, we report a new member of RhoGEF, WGEF, which has the classical structure of DH-PH domain and a C-terminal SH3 domain. WGEF was shown to activate RhoA, Cdc42, and Rac1 by pulldown assay, and forced expression of WGEF resulted in marked rearrangement of the actin cytoskeleton, which is typically seen by the activation of RhoA, Cdc42, and Rac1. WGEF was highly expressed in intestine and also in liver, heart and kidney, which may suggest the involvement of WGEF in the development and functions of these organs. The expression pattern may also suggest the possible importance of WGEF in the understanding of diseases based on metabolic disorder. 相似文献
999.
1000.