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S Braig R M Wiedmann J Liebl M Singer R Kubisch L Schreiner B A Abhari E Wagner U Kazmaier S Fulda A M Vollmar 《Cell death & disease》2014,5(1):e1001
Tubulin-binding agents such as taxol, vincristine or vinblastine are well-established drugs in clinical treatment of metastatic cancer. However, because of their highly complex chemical structures, the synthesis and hence the supply issues are still quite challenging. Here we set on stage pretubulysin, a chemically accessible precursor of tubulysin that was identified as a potent microtubule-binding agent produced by myxobacteria. Although much simpler in chemical structure, pretubulysin abrogates proliferation and long-term survival as well as anchorage-independent growth, and also induces anoikis and apoptosis in invasive tumor cells equally potent to tubulysin. Moreover, pretubulysin posseses in vivo efficacy shown in a chicken chorioallantoic membrane (CAM) model with T24 bladder tumor cells, in a mouse xenograft model using MDA-MB-231 mammary cancer cells and finally in a model of lung metastasis induced by 4T1 mouse breast cancer cells. Pretubulysin induces cell death via the intrinsic apoptosis pathway by abrogating the expression of pivotal antiapoptotic proteins, namely Mcl-1 and Bcl-xL, and shows distinct chemosensitizing properties in combination with TRAIL in two- and three-dimensional cell culture models. Unraveling the underlying signaling pathways provides novel information: pretubulysin induces proteasomal degradation of Mcl-1 by activation of mitogen-activated protein kinase (especially JNK (c-Jun N-terminal kinase)) and phosphorylation of Mcl-1, which is then targeted by the SCFFbw7 E3 ubiquitin ligase complex for ubiquitination and degradation. In sum, we designate the microtubule-destabilizing compound pretubulysin as a highly promising novel agent for mono treatment and combinatory treatment of invasive cancer. 相似文献
3.
George V. Sharonov Eduard V. Bocharov Peter M. Kolosov Maria V. Astapova Alexander S. Arseniev Alexey V. Feofanov 《The Journal of biological chemistry》2014,289(21):14955-14964
The EphA2 receptor tyrosine kinase plays a central role in the regulation of cell adhesion and guidance in many human tissues. The activation of EphA2 occurs after proper dimerization/oligomerization in the plasma membrane, which occurs with the participation of extracellular and cytoplasmic domains. Our study revealed that the isolated transmembrane domain (TMD) of EphA2 embedded into the lipid bicelle dimerized via the heptad repeat motif L535X3G539X2A542X3V546X2L549 rather than through the alternative glycine zipper motif A536X3G540X3G544 (typical for TMD dimerization in many proteins). To evaluate the significance of TMD interactions for full-length EphA2, we substituted key residues in the heptad repeat motif (HR variant: G539I, A542I, G553I) or in the glycine zipper motif (GZ variant: G540I, G544I) and expressed YFP-tagged EphA2 (WT, HR, and GZ variants) in HEK293T cells. Confocal microscopy revealed a similar distribution of all EphA2-YFP variants in cells. The expression of EphA2-YFP variants and their kinase activity (phosphorylation of Tyr588 and/or Tyr594) and ephrin-A3 binding were analyzed with flow cytometry on a single cell basis. Activation of any EphA2 variant is found to occur even without ephrin stimulation when the EphA2 content in cells is sufficiently high. Ephrin-A3 binding is not affected in mutant variants. Mutations in the TMD have a significant effect on EphA2 activity. Both ligand-dependent and ligand-independent activities are enhanced for the HR variant and reduced for the GZ variant compared with the WT. These findings allow us to suggest TMD dimerization switching between the heptad repeat and glycine zipper motifs, corresponding to inactive and active receptor states, respectively, as a mechanism underlying EphA2 signal transduction. 相似文献
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Anna Pugatshova ülle Kikas Margit Prüssel Aivo Reinart Eduard Tamm et al. 《Plant Growth Regulation》1991,10(2):177-178
Book Review
Principles of environmental physicsJ.L. Monteith and M.H. Unsworth Second edition. London: Edward Arnold, 1990. xii + 291 pages. £30.00 (hardback), £14.95 (paperback). ISBN 0-7131-2931-X 相似文献6.
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Growth responses of Neurospora crassa to increased partial pressures of the noble gases and nitrogen 总被引:2,自引:0,他引:2
Buchheit, R. G. (Union Carbide Corp., Tonawanda, N.Y.), H. R. Schreiner, and G. F. Doebbler. Growth responses of Neurospora crassa to increased partial pressures of the noble gases and nitrogen. J. Bacteriol. 91:622-627. 1966.-Growth rate of the fungus Neurospora crassa depends in part on the nature of metabolically "inert gas" present in its environment. At high partial pressures, the noble gas elements (helium, neon, argon, krypton, and xenon) inhibit growth in the order: Xe > Kr> Ar > Ne > He. Nitrogen (N(2)) closely resembles He in inhibitory effectiveness. Partial pressures required for 50% inhibition of growth were: Xe (0.8 atm), Kr (1.6 atm), Ar (3.8 atm), Ne (35 atm), and He ( approximately 300 atm). With respect to inhibition of growth, the noble gases and N(2) differ qualitatively and quantitatively from the order of effectiveness found with other biological effects, i.e., narcosis, inhibition of insect development, depression of O(2)-dependent radiation sensitivity, and effects on tissue-slice glycolysis and respiration. Partial pressures giving 50% inhibition of N. crassa growth parallel various physical properties (i.e., solubilities, solubility ratios, etc.) of the noble gases. Linear correlation of 50% inhibition pressures to the polarizability and of the logarithm of pressure to the first and second ionization potentials suggests the involvement of weak intermolecular interactions or charge-transfer in the biological activity of the noble gases. 相似文献
9.
The gravitational work of breathing was determined by measuring the vertical motion of body mass. The subject, seated or lying supine on a force platform, performed breathing maneuvers in which rib cage volume (Vrc) and abdominal volume (Vab) were changed in varying proportions. The increment in the vertical force exerted on the platform and Vrc and Vab were measured over the course of each maneuver. The force signal was integrated twice with respect to time to obtain the change in the product of mass and height of the subject. This was multiplied by the gravitational acceleration to obtain the change in the gravitational potential (Ug). Simultaneous values of Ug, Vrc, and Vab were taken from the data, and the values of the coefficients for which the following equation best fit these values were determined: Ug = a1 Vrc + a2 Vab + (1/2)a11 Vrc2 + a12 Vrc Vab + (1/2)a22 Vab2. The coefficients a1 and a2 can be interpreted as the values of the expiratory gravitational forces on the rib cage and abdomen, respectively. In the seated posture, the force on the rib cage is expiratory and the force on the abdomen is inspiratory; the magnitudes of both are approximately 8 cmH2O. In the supine posture, both are expiratory forces of approximately 9 cmH2O. The coefficients of the quadratic terms in Ug are all positive, and the gravitational work per unit volume of chest wall expansion increases with increasing volume in both postures. The coefficients of the quadratic terms can be interpreted as gravitational contributions to the elastances of the compartments. 相似文献
10.
C. A. Schreiner D. A. Edwards R. H. McKee M. Swanson Z. A. Wong S. Schmitt P. Beatty 《Cell biology and toxicology》1989,5(2):169-188
Catalytic reforming is a refining process that converts naphthenes to aromatics by dehydrogenation to make higher octane gasoline blending components. A portion of this wide boiling range hydrocarbon stream can be separated by distillation and used for other purposes. One such application is a mixture of predominantly 9-carbon aromatic molecules (C9 aromatics, primarily isomers of ethyltoluene and trimethylbenzene), which is removed and used as a solvent — high-flash aromatic naphtha. A program was initiated to assess the toxicological properties of high-flash aromatic naphtha since there may be human exposure through inhalation or external body contact. The current study was conducted partly to assess the potential for mutagenic activity and also to assist in an assessment of carcinogenic potential. The specific tests utilized included the Salmonella/mammalian microsome mutagenicity assay, the hypoxanthine-guanine phosphoribosyl transferase (HGPRT) forward mutation assay in CHO cells, in vitro chromosome aberration and sister chromatid exchange (SCE) assays in CHO cells, and an in vivo chromosome aberration assay in rat bone marrow.There was no evidence that high-flash aromatic naphtha was either a gene or chromosomal mutagen. Thus it is unlikely to be a genotoxic carcinogen.Abbreviations Brdu
5-Bromo-2-deoxyuridine
- C9
Aromatic species with 9 carbons (i.e., ethyl toluene and trimethyl benzene isomers)
- CE
Cloning efficiency
- CHO
Chinese hamster embryo
- CP
Cyclophosphamide
- DMSO
Dimethyl sulfoxide
- HGPRT
Hypoxanthine-guanine phosphoribosyl transferase
- HVAC
Heating, Ventilation, Air Conditioning
- 3MC
3 Methylcholanthrene
- MMC
Mitomycin C
- MMS
Methyl methanesulfonate
- S9
S9 Mammalian microsomal enzyme activation mixture
- SCE
Sister chromatid exchange 相似文献