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51.
LE Lain R Barrell KJ Saeed GS Nicholls PJ Simons C Kirby A Smith HJ 《Journal of enzyme inhibition and medicinal chemistry》2002,17(2):93-100
The 7-hydroxycoumarins, umbelliferone and 4-methylumbelliferone (IC50 = 1.4 and 1.9 microM, respectively) were potent inhibitors of human testes microsomal 17beta-HSD (type 3) enzyme whereas 7-methoxycoumarin, 4-hydroxycoumarin and 7-ethoxycoumarin had little or no inhibitory activity. Analogues of the weak inhibitory triphenylethenes tamoxifen and clomiphene but lacking the basic substituent, were weak inhibitors of the human microsomal enzyme. Inhibitory activity was improved by replacement of the triphenylethene structure with a triphenylmethyl (17, 52.6% inhibition) or phenylpropyl (16, 94.8%, IC50 = 42.1 microM) skeleton. Further studies on tamoxifen using rat testes microsomal 17beta-HSD showed that the inhibition was time-dependent and irreversible but not specifically mechanism-based. 相似文献
52.
A dominant negative protein kinase C zeta subspecies blocks NF-kappa B activation. 总被引:25,自引:2,他引:23
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M T Diaz-Meco E Berra M M Municio L Sanz J Lozano I Dominguez V Diaz-Golpe M T Lain de Lera J Alcamí C V Payá et al. 《Molecular and cellular biology》1993,13(8):4770-4775
Nuclear factor kappa B (NF-kappa B) plays a critical role in the regulation of a number of genes. NF-kappa B is a heterodimer of 50- and 65-kDa subunits sequestered in the cytoplasm complexed to inhibitory protein I kappa B. Following stimulation of cells, I kappa B dissociates from NF-kappa B, allowing its translocation to the nucleus, where it carries out the transactivation function. The precise mechanism controlling NF-kappa B activation and the involvement of members of the protein kinase C (PKC) family of isotypes have previously been investigated. It was found that phorbol myristate acetate, (PMA) which is a potent stimulant of phorbol ester-sensitive PKC isotypes, activates NF-kappa B. However, the role of PMA-sensitive PKCs in vivo is not as apparent. It has recently been demonstrated in the model system of Xenopus laevis oocytes that the PMA-insensitive PKC isotype, zeta PKC, is a required step in the activation of NF-kappa B in response to ras p21. We demonstrate here that overexpression of zeta PKC is by itself sufficient to stimulate a permanent translocation of functionally active NF-kappa B into the nucleus of NIH 3T3 fibroblasts and that transfection of a kinase-defective dominant negative mutant of zeta PKC dramatically inhibits the kappa B-dependent transactivation of a chloramphenicol acetyltransferase reporter plasmid in NIH 3T3 fibroblasts. All these results support the notion that zeta PKC plays a decisive role in NF-kappa B regulation in mammalian cells. 相似文献
53.
A Adoutte P Delgado A Fleury N Levilliers M C Lainé M C Marty E Boisvieux-Ulrich D Sandoz 《Biology of the cell / under the auspices of the European Cell Biology Organization》1991,71(1-2):227-245
The diversity of microtubular networks was analyzed in quail oviduct and in Paramecium cells using conventional and confocal immunofluorescence as well as pre- and post-embedding EM immunocytochemistry with a variety of anti-tubulin antibodies. The 6-11B-1 monoclonal antibody, specific for the post-translational acetylation of Lys 40 of alpha-tubulin, and a polyclonal antibody raised against Paramecium axonemal tubulin (anti-PA tubulin antibody) both decorated stable microtubular arrays in Paramecium ie ciliary axonemes and a set of microtubular bundles associated with the cortex, suggesting that the two antibodies may be directed against the same epitope. However, several differences in the immunocytological patterns yielded by each antibody on the two cell types were evident. For example, in quail, as in all other Metazoa, the anti-PA tubulin antibody only decorated axonemes enclosed in normal ciliary membrane while it was unreactive on cytoplasmic tubulins. Immunoblotting of peptide maps of axonemal tubulins demonstrated that the epitopes of the two antibodies were indeed completely different. Double immunolabelling of dividing paramecia using a universal anti-tubulin antibody and the anti-PA tubulin one revealed that all newly assembled microtubular arrays were first detected by the universal antibody and, only shortly afterwards, by the anti-PA tubulin one. This provided a strong indication that the anti-PA tubulin antibody is directed against a post-translational modification taking place on already assembled microtubules (MTs) (as previously known to be the case for acetylation and detyrosination). In taxol-treated quail cells undergoing ciliogenesis, massive assembly of MTs and even axonemes occurred in the cytoplasm. These MTs were not decorated by the anti-PA tubulin antibody however, suggesting that in Metazoa the post-translational modification can only take place within the ciliary lumen. The present work provides one further mechanism for generating MT immunological and biochemical diversity post-translationally; this may account for the high multiplicity of tubulin isoforms observed in ciliates which contain very little if any genetic diversity of tubulin genes. 相似文献
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55.
MEK/ERK signaling pathway regulates the expression of Bcl-2, Bcl-X(L), and Mcl-1 and promotes survival of human pancreatic cancer cells 总被引:18,自引:0,他引:18
Boucher MJ Morisset J Vachon PH Reed JC Lainé J Rivard N 《Journal of cellular biochemistry》2000,79(3):355-369
BACKGROUND AND AIMS: Growth factors are well known for their participation in the regulation of cell proliferation and survival. However, the intracellular signaling pathways by which growth factors promote survival are still poorly understood. In the present study, using the MIA PaCa-2 cell line, a well-established model of pancreatic cancer cells, we analyzed the roles of ERK1/2 activities in the regulation of cell survival and investigated some of the mechanisms involved. METHODS: The ability of the MEK inhibitor PD98059 to modulate survival of the MIA PaCa-2 cells was evaluated, and the responses were correlated with expression of Bcl-2 homologs and caspases 1, 3, 6, 8, and 9 activities. RESULTS: Herein, we showed that inhibition of ERK1/2 activities caused (1) a G1 arrest; (2) a down-regulation of the expression levels of the anti-apoptotic homologs Bcl-2, Mcl-1, and Bcl-X(L) without affecting the pro-apoptotic levels of Bax and Bak; (3) a promotion of caspases 3, 6, 8, and 9 activities; (4) a stimulation of PARP cleavage; and (5) a programmed cell death by apoptosis. CONCLUSION: Our data suggest that activation of the ERK pathway functions to protect pancreatic tumor cells from apoptosis as well as to regulate their progression in the cell cycle. 相似文献
56.
In a screening programme for inhibitors of human testis 17beta-hydroxysteroid dehydrogenase (17beta-HSD type 3), as potential agents for the treatment of hormone-dependent prostatic cancer, we have used crude human testis microsomal 17beta-hydroxysteroid dehydrogenase as a convenient source of the enzyme. Crude human enzyme was shown to have a similar substrate profile to recombinant Type 3 17beta-HSD from the same source as determined by the low Km/Vmax ratio for the reduction of androstenedione compared to the oxidation of testosterone, and a low level of activity in reduction of oestrone. Screening of a wide range of compounds of different structural types as potential inhibitors of the microsomal enzyme in the reduction step revealed that certain p-benzoquinones and flavones/isoflavones were potent inhibitors of the enzyme, diphenyl-p-benzoquinone (2.7 microM), phenyl-p-benzoquinone (5.7 microM), 7-hydroxyflavone (9.0 microM), baicalein (9.3 microM) and biochanin A (10.8 microM). Some structure-activity relationships within the flavone/isoflavone series are discussed. Studies with rat testis microsomal 17beta-HSD showed that it differed from the human enzyme mainly in its greater ability to accept oestrone as substrate and the pH-optimum for oxidation of testosterone. It was found to be much less sensitive to inhibition by the compounds studied so negating it use as a more readily available tissue for the screening of potential inhibitors. 相似文献
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