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71.
Wege H Heim D Lütgehetmann M Dierlamm J Lohse AW Brümmendorf TH 《Molecular cancer research : MCR》2011,9(9):1222-1231
Hepatocarcinogenesis is a multistep process driving the progressive transformation of normal liver cells into highly malignant derivatives. Unlimited proliferation and telomere maintenance have been recognized as prerequisites for the development of liver cancer. Moreover, recent studies identified illegitimate β-catenin signaling as relevant hit in a considerable subset of patients. To further investigate the currently not well-understood malignant evolution driven by telomerase and β-catenin, we monitored cytogenetic and phenotypic alterations in untransformed telomerase-immortalized human fetal hepatocytes following forced activation of β-catenin signaling. As expected, constitutive activation of β-catenin signaling significantly enhanced proliferation with decreasing serum dependence. Previously intact contact inhibition was almost completely eliminated. Interestingly, after several passages in cell culture, immortalized clones with dominant-positive β-catenin signaling acquired additional chromosomal aberrations, in particular translocations, anchorage-independent growth capabilities, and formed tumors in athymic nude mice. In further support for the driving role of β-catenin during hepatocarcinogenesis, improved colony growth in soft agar and accelerated tumor formation was also confirmed in Huh7 cells following stable expression of the constitutively active S33Y β-catenin mutant. Telomerase inhibition showed that short-term expansion of transformed clones was not telomerase dependent. Finally, cancer pathway profiling in derived tumors revealed upregulation of characteristic genes associated with invasion and angiogenesis. In conclusion, illegitimate activation of β-catenin signaling enhances the transformation from immortalization to malignant growth in human fetal hepatocytes. Our data functionally confirm a permissive role for β-catenin signaling in the initial phase of hepatocarcinogenesis. 相似文献
72.
Ansgar Hakvoort Matthias Haselbach Joachim Wegener Dirk Hoheisel Hans-Joachim Galla 《Journal of neurochemistry》1998,71(3):1141-1150
Abstract: The influence of culture conditions on the development of normal characteristics of the choroid plexus epithelium has been investigated in vitro with respect to polarity, barrier properties, transport, and secretory activity. Withdrawal of serum supplement in the culture medium of cells grown on filters caused morphologically visible changes by an increased trimming of microvilli at the apical membrane side, which is accompanied by an increased expression of the Na+ ,K+ -ATPase. Moreover cells under serum-free conditions exhibit structural changes in tight junctional zonula occludens protein-1 (ZO-1) organization, a reduced permeability, and a drastically increased electrical resistance from 150 Ω· cm2 in the presence of serum to 1,500 Ω· cm2 after serum withdrawal. Under these conditions, cell monolayers are able to build up a transcellular proton gradient and to secrete fluid into the upper (apical) filter compartment, which is accompanied by a polarized secretion of proteins like transthyretin. Active transport of the dyes fluorescein and phenol red by the organic anion transporter is found to be driven by the Na+ ,K+ -ATPase. We come to the conclusion that removal of serum favors the differentiation process of the plexus epithelium in vitro, which brings the cell culture model closer to the physiological situation in vivo. We present preliminary evidence that epidermal growth factor may be one component in serum preventing the proper in vitro differentiation. 相似文献
73.
Eugenia M. del Pino Herbert Steinbeisser Ansgar Hofmann Christine Dreyer Margarita Campos Michael F. Trendelenburg 《Differentiation; research in biological diversity》1986,32(1):24-33
Abstract. The dissimilarities between oocytes of the eggbrooding frog, Gastrotheca riobambae , and Xenopus laevis suggest that oogenesis is modified according to the mode of reproduction. Oocytes of G. riobambae are large, yolky, and measure about 3 mm in diameter. In spite of the large oocyte size of Gastrotheca , the amplification of ribosomal genes, the number of nucleoli, and the amount of 18S and 28S rRNA are lower than in Xenopus oocytes. In Gastrotheca , the lower RNA content of oocytes is associated with a slow rate of development. A prolonged period of development is possible due to the protection given by the maternal pouch. 相似文献
74.
We developed a general approach that allows unnatural amino acids with diverse physicochemical and biological properties to be genetically encoded in mammalian cells. A mutant Escherichia coli aminoacyl-tRNA synthetase (aaRS) is first evolved in yeast to selectively aminoacylate its tRNA with the unnatural amino acid of interest. This mutant aaRS together with an amber suppressor tRNA from Bacillus stearothermophilus is then used to site-specifically incorporate the unnatural amino acid into a protein in mammalian cells in response to an amber nonsense codon. We independently incorporated six unnatural amino acids into GFP expressed in CHO cells with efficiencies up to 1 mug protein per 2 x 10(7) cells; mass spectrometry confirmed a high translational fidelity for the unnatural amino acid. This methodology should facilitate the introduction of biological probes into proteins for cellular studies and may ultimately facilitate the synthesis of therapeutic proteins containing unnatural amino acids in mammalian cells. 相似文献
75.
Buchstaller HP Eggenweiler HM Sirrenberg C Grädler U Musil D Hoppe E Zimmermann A Schwartz H März J Bomke J Wegener A Wolf M 《Bioorganic & medicinal chemistry letters》2012,22(13):4396-4403
Inhibitors of the Hsp90 molecular chaperone are showing considerable promise as potential molecular therapeutic agents for the treatment of cancer. Here we describe the identification of novel small molecular weight inhibitors of Hsp90 using a fragment based approach. Fragments were selected by docking, tested in a biochemical assay and the confirmed hits were crystallized. Information gained from X-ray structures of these fragments and other chemotypes was used to drive the fragment evolution process. Optimization of these high μM binders resulted in 3-benzylindazole derivatives with significantly improved affinity and anti-proliferative effects in different human cancer cell lines. 相似文献
76.
Siemer AB Ritter C Steinmetz MO Ernst M Riek R Meier BH 《Journal of biomolecular NMR》2006,34(2):75-87
The partial 15N and 13C solid-state NMR resonance assignment of the HET-s prion protein fragment 218–289 in its amyloid form is presented. It is
based on experiments measured at MAS frequencies in the range of 20–40 kHz using exclusively adiabatic polarization-transfer
schemes. The resonance assignment within each residue is based on two-dimensional 13C––13C correlation spectra utilizing the DREAM mixing scheme. The sequential linking of the assigned residues used a set of two-
and three-dimensional 15N––13C correlation experiments. Almost all cross peaks visible in the spectra are assigned, but only resonances from 43 of the
78 amino-acid residues could be detected. The missing residues are thought to be highly disordered and/or highly dynamic giving
rise to broad resonance lines that escaped detection in the experiments applied. The line widths of the observed resonances
are narrow and comparable to line widths observed in micro-crystalline samples. The 43 assigned residues are located in two
fragments of about 20 residues.
Electronic Supplementary Material Supplementary material is available for this article at and is accessible for authorized users. 相似文献
77.
Fujisaki W Koene A Arnold D Johnston A Nishida S 《Proceedings. Biological sciences / The Royal Society》2006,273(1588):865-874
We examined whether the detection of audio-visual temporal synchrony is determined by a pre-attentive parallel process, or by an attentive serial process using a visual search paradigm. We found that detection of a visual target that changed in synchrony with an auditory stimulus was gradually impaired as the number of unsynchronized visual distractors increased (experiment 1), whereas synchrony discrimination of an attended target in a pre-cued location was unaffected by the presence of distractors (experiment 2). The effect of distractors cannot be ascribed to reduced target visibility nor can the increase in false alarm rates be predicted by a noisy parallel processing model. Reaction times for target detection increased linearly with number of distractors, with the slope being about twice as steep for target-absent trials as for target-present trials (experiment 3). Similar results were obtained regardless of whether the audio-visual stimulus consisted of visual flashes synchronized with amplitude-modulated pips, or of visual rotations synchronized with frequency-modulated up-down sweeps. All of the results indicate that audio-visual perceptual synchrony is judged by a serial process and are consistent with the suggestion that audio-visual temporal synchrony is detected by a 'mid-level' feature matching process. 相似文献
78.
Roland Moll Evelyn Sievers Bettina Hämmerling Ansgar Schmidt Mareike Barth Caecilia Kuhn Christine Grund Ilse Hofmann Werner W. Franke 《Cell and tissue research》2009,335(1):109-141
The lymph node sinus are channel structures of unquestionable importance in immunology and pathology, specifically in the
filtering of the lymph, the transport and processing of antigens, the adhesion and migration of immune cells, and the spread
of metastatic cancer cells. Our knowledge of the cell and molecular biology of the sinus-forming cells is still limited, and
the origin and biological nature of these cells have long been a matter of debate. Here, we review the relevant literature
and present our own experimental results, in particular concerning molecular markers of intercellular junctions and cell differentiation.
We show that both the monolayer cells lining the sinus walls and the intraluminal virgultar cell meshwork are indeed different
morphotypes of the same basic endothelial cell character, as demonstrated by the presence of a distinct spectrum of general
and lymphatic endothelial markers, and we therefore refer to these cells as sinus endothelial/virgultar cells (SEVCs). These
cells are connected by unique adhering junctions, termed complexus adhaerentes, characterized by the transmembrane glycoprotein VE-cadherin, combined with the desmosomal plaque protein desmoplakin, several
adherens junction plaque proteins including α- and β-catenin and p120 catenin, and components of the tight junction ensemble,
specifically claudin-5 and JAM-A, and the plaque protein ZO-1. We show that complexus adhaerentes are involved in the tight three-dimensional integration of the virgultar network of SEVC processes along extracellular guidance
structures composed of paracrystalline collagen bundle “stays”. Overall, the SEVC system might be considered as a local and
specific modification of the general lymphatic vasculature system. Finally, physiological and pathological alterations of
the SEVC system will be presented, and the possible value of the molecular markers described in histological diagnoses of
autochthonous lymph node tumors will be discussed.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.
相似文献
Werner W. FrankeEmail: |
79.
Benjamin Fränzel Frank Fischer Christian Trötschel Ansgar Poetsch Dirk Wolters Dr. 《Proteomics》2009,9(8):2263-2272
We established a single consecutive strategy which assigned the most comprehensive number of integral membrane proteins from Gram‐positive bacteria to date. For this purpose, we adapted a biphasic partitioning system for the biotechnologically intensively used Corynebacterium glutamicum and proved for the first time that such a system is well suited for quantitative comparison. 297 integral membrane proteins were identified by our integrated approach, which depletes stringently cytosolic proteins. In combination with our previously developed SIMPLE strategy, our data comprise 61% (374 integral membrane proteins) of the entire membrane proteome, which aims towards an almost comprehensive coverage. Wild type and a production strain of C. glutamicum were compared by 15N metabolic labelling and quantitation was obtained by spectral counting and peak areas. Both quantification strategies display a consistent trend in up or downregulation of proteins. Nevertheless, spectral counting often provides results indicating a much stronger regulation compared to ProRata values. Either spectral counting seems to exaggerate protein regulation or ProRata tends to attenuate the information about the regulation level. We highlight some of the biologically relevant candidates, which prove that our approach helps to give a deeper quantitative insight towards the understanding of transport and other membrane associated processes, important for strain development of C. glutamicum. 相似文献
80.
Corinna Schirling Christiane Heseding Franziska Heise Dörthe Kesper Ansgar Klebes Ludger Klein-Hitpass Andrea Vortkamp Daniel Hoffmann Harald Saumweber Ann E. Ehrenhofer-Murray 《Chromosoma》2010,119(1):99-113
The MYST histone acetyltransferase (HAT) dTip60 is part of a multimeric protein complex that unites both HAT and chromatin
remodeling activities. Here, we sought to gain insight into the biological functions of dTip60. Strong ubiquitous dTip60 knock-down
in flies was lethal, whereas knock-down in the wing imaginal disk led to developmental defects in the wing. dTip60 localized
to the nucleus in early embryos and was present in a large number of interbands on polytene chromosomes. Genome-wide expression
analysis upon depletion of dTip60 in cell culture showed that it regulated a large number of genes in Drosophila, among which those with chromatin-related functions were highly enriched. Surprisingly, a significant portion of these genes
were upregulated upon dTip60 loss, indicating that dTip60 has repressive as well as activating functions. dTip60 protein was
directly located at promoter regions of a subset of repressed genes, suggesting a direct role in gene repression. Comparison
of the gene expression signature of dTip60 downregulation with that of histone deacetylase inhibition with trichostatin A
revealed a significant correlation, suggesting that the dTip60 complex recruits an HDAC-containing complex to regulate gene
expression in the Drosophila genome. 相似文献