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  • Articles  (23)
  • 2010-2014  (23)
  • 2012  (23)
  • 1
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    Enhanced hepatocarcinogenesis in mouse models and human HCC by coordinate KLF6 depletion and increased mRNA splicing (2012)
    Wiley-Blackwell
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    Publication Date: 2012-05-02
    Description: Background: KLF6-SV1 ( SV1 ), the major splice variant of KLF6 , antagonizes the KLF6 tumor suppressor by an unknown mechanism. Decreased KLF6 expression in human hepatocellular carcinoma (HCC) correlates with increased mortality, but the contribution of increased SV1 is unknown. We sought to define the impact of SV1 on human outcomes and experimental murine hepatocarcinogenesis, and to elucidate its mechanism of action. Results: In HCV-related HCC, an increased ratio of SV1/KLF6 within the tumor was associated with more features of more advanced disease. Six months after a single injection of diethylnitrosamine (DEN), SV1 hepatocyte transgenic mice developed more histologically advanced tumors, whereas Klf6 -depleted mice developed bigger tumors compared to the Klf6 fl(+/+) control mice. Nine months after DEN, SV1 transgenic-mice with Klf6 -depletion had the greatest tumor burden. Primary mouse hepatocytes from both the SV1 transgenic animals and those with hepatocyte-specific Klf6 depletion displayed increased DNA synthesis, with an additive effect in hepatocytes harboring both SV1 over-expression and Klf6 depletion. Parallel results were obtained by viral SV1-transduction- and depletion of Klf6 through adenovirus-Cre infection of primary Klf6 fl(+/+) hepatocytes. Increased DNA synthesis was due to both enhanced cell proliferation and increased ploidy. Co-IP studies in 293T cells uncovered a direct interaction of transfected SV1 with KLF6 . Accelerated KLF6 degradation in the presence of SV1 was abrogated by the proteasome inhibitor MG132. Conclusion: Increased SV1/KLF6 ratio correlates with more aggressive HCC. In mice, an increased SV1/KLF6 ratio, generated either by increasing SV1, decreasing KLF6, or both, accelerates hepatic carcinogenesis. Moreover, SV1 binds directly to KLF6 and accelerates its degradation. These findings represent a novel mechanism underlying the antagonism of tumor suppressor gene function by a splice variant of the same gene. (H EPATOLOGY 2012.)
    Print ISSN: 0270-9139
    Electronic ISSN: 1527-3350
    Topics: Medicine
    Published by Wiley-Blackwell on behalf of The American Association for the Study of Liver Diseases.
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  • 2
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    Visual Aids for Multimodal Treatment Options to Support Decision Making of Patients with Colorectal Cancer (2012)
    BioMed Central
    Details
    Publication Date: 2012-10-24
    Description: Background: A variety of multimodal treatment options are available for colorectal cancer and many patients want to be involved in decisions about their therapies. However, their desire for autonomy is limited by lack of disease-specific knowledge. Visual aids may be helpful tools to present complex data in an easy-to-understand, graphic form to lay persons. The aim of the present study was to evaluate the treatment preferences of healthy persons and patients using visual aids depicting multimodal treatment options for colorectal cancer. Methods: We designed visual aids for treatment scenarios based on four key studies concerning multimodal treatment of colorectal cancer. The visual aids were composed of diagrams depicting outcome parameters and side effects of two treatment options. They were presented to healthy persons (n = 265) and to patients with colorectal cancer (n = 102). Results: Most patients and healthy persons could make immediate decisions after seeing the diagrams (range: 88% -- 100%). Patients (79%) chose the intensive-treatment option in the scenario with a clear survival benefit. In scenarios without survival benefit, all groups clearly preferred the milder treatment option (range: 78% - 90%). No preference was seen in the scenario depicting equally intense treatment options with different timing (neoadjuvant vs. adjuvant) but without survival benefit. Conclusions: Healthy persons' and patients' decisions using visual aids seem to be influenced by quality-of-life aspects rather than recurrence rates especially in situations without survival benefit. In the future visual aids may help to improve the management of patients with colorectal cancer.
    Electronic ISSN: 1472-6947
    Topics: Computer Science , Medicine
    Published by BioMed Central
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  • 3
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    Structural basis for Arl3-specific release of myristoylated ciliary cargo from UNC119 (2012)
    Nature Publishing Group (NPG)
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    Publication Date: 2012-10-18
    Description: The EMBO Journal 31, 4085 (2012). doi:10.1038/emboj.2012.257 Authors: Shehab A Ismail, Yong-Xiang Chen, Mandy Miertzschke, Ingrid R Vetter, Carolin Koerner & Alfred Wittinghofer Access to the ciliary membrane for trans-membrane or membrane-associated proteins is a regulated process. Previously, we have shown that the closely homologous small G proteins Arl2 and Arl3 allosterically regulate prenylated cargo release from PDEδ. UNC119/HRG4 is responsible for ciliary delivery of myristoylated cargo. Here,
    Keywords: Arfsciliaprotein traffickingreleasing factorssmall G proteins
    Print ISSN: 0261-4189
    Electronic ISSN: 1460-2075
    Topics: Biology , Medicine
    Published by Nature Publishing Group (NPG) on behalf of The European Molecular Biology Organization (EMBO).
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  • 4
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    Structure of human {alpha}TAT1 [Biochemistry] (2012)
    National Academy of Sciences
    Details
    Publication Date: 2012-11-28
    Description: Acetylation of lysine residues is an important posttranslational modification found in all domains of life. α-tubulin is specifically acetylated on lysine 40, a modification that serves to stabilize microtubules of axons and cilia. Whereas histone acetyltransferases have been extensively studied, there is no structural and mechanistic information available on α-tubulin...
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 5
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    Identification and characterization of the bacterial etiology of clinically problematic acute otitis media after tympanocentesis or spontaneous otorrhea in German children (2012)
    BioMed Central
    Details
    Publication Date: 2012-11-21
    Description: Background: Acute Otitis Media (AOM) is an important and common disease of childhood. Bacteria isolated from cases of clinically problematic AOM in German children were identified and characterized Methods: In a prospective non-interventional study in German children between 3 months and less than 60 months of age with Ear, Nose and Throat Specialist --confirmed AOM, middle ear fluid was obtained by tympanocentesis (when clinically indicated) or by careful sampling of otorrhea through/at an existing perforation. Results: In 100 children with severe AOM, Haemophilus influenzae was identified in 21% (18/21, 85.7% were non-typeable [NTHi]), Streptococcus pneumoniae in 10%, S. pyogenes in 13% and Moraxella catarrhalis in 1%. H. influenzae was the most frequently identified pathogen in children from 12 months of age. H. influenzae and S. pneumoniae were equally prevalent in children aged 3--11 months, but S. pyogenes was most frequently isolated in this age group. NTHi AOM disease appeared prevalent in all ages. Conclusions: NTHi, S. pneumoniae and S. pyogenes are implicated as important causes of complicated AOM in children in Germany. NTHi disease appears prevalent in all ages. The impact of vaccination to prevent NTHi and S. pneumoniae AOM may be substantial in this population and is worth investigating.
    Electronic ISSN: 1471-2334
    Topics: Medicine
    Published by BioMed Central
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  • 6
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    Ciguatoxins activate specific cold pain pathways to elicit burning pain from cooling (2012)
    Nature Publishing Group (NPG)
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    Publication Date: 2012-10-04
    Description: Ciguatoxins activate specific cold pain pathways to elicit burning pain from cooling The EMBO Journal 31, 3795 (2012). doi:10.1038/emboj.2012.207 Authors: Irina Vetter, Filip Touska, Andreas Hess, Rachel Hinsbey, Simon Sattler, Angelika Lampert, Marina Sergejeva, Anastasia Sharov, Lindon S Collins, Mirjam Eberhardt, Matthias Engel, Peter J Cabot, John N Wood, Viktorie Vlachová, Peter W Reeh, Richard J Lewis & Katharina Zimmermann Ciguatoxins are sodium channel activator toxins that cause ciguatera, the most common form of ichthyosarcotoxism, which presents with peripheral sensory disturbances, including the pathognomonic symptom of cold allodynia which is characterized by intense stabbing and burning pain in response to mild cooling. We show that
    Keywords: ciguatoxincold allodyniaNavnociceptorTRPA1
    Print ISSN: 0261-4189
    Electronic ISSN: 1460-2075
    Topics: Biology , Medicine
    Published by Nature Publishing Group (NPG) on behalf of The European Molecular Biology Organization (EMBO).
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  • 7
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    Developmental regulation of N-terminal H2B methylation in Drosophila melanogaster (2012)
    Oxford University Press
    Details
    Publication Date: 2012-02-28
    Description: Histone post-translational modifications play an important role in regulating chromatin structure and gene expression in vivo . Extensive studies investigated the post-translational modifications of the core histones H3 and H4 or the linker histone H1. Much less is known on the regulation of H2A and H2B modifications. Here, we show that a major modification of H2B in Drosophila melanogaster is the methylation of the N-terminal proline, which increases during fly development. Experiments performed in cultured cells revealed higher levels of H2B methylation when cells are dense, regardless of their cell cycle distribution. We identified dNTMT (CG1675) as the enzyme responsible for H2B methylation. We also found that the level of N-terminal methylation is regulated by dART8, an arginine methyltransferase that physically interacts with dNTMT and asymmetrically methylates H3R2. Our results demonstrate the existence of a complex containing two methyltransferases enzymes, which negatively influence each other’s activity.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 8
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    Revealing conformational substates of lipidated N-Ras protein by pressure modulation [Biophysics and Computational Biology] (2012)
    National Academy of Sciences
    Details
    Publication Date: 2012-01-12
    Description: Regulation of protein function is often linked to a conformational switch triggered by chemical or physical signals. To evaluate such conformational changes and to elucidate the underlying molecular mechanisms of subsequent protein function, experimental identification of conformational substates and characterization of conformational equilibria are mandatory. We apply pressure modulation in combination with FTIR spectroscopy to reveal equilibria between spectroscopically resolved substates of the lipidated signaling protein N-Ras. Pressure has the advantage that its thermodynamic conjugate is volume, a parameter that is directly related to structure. The conformational dynamics of N-Ras in its different nucleotide binding states in the absence and presence of a model biomembrane was probed by pressure perturbation. We show that not only nucleotide binding but also the presence of the membrane has a drastic effect on the conformational dynamics and selection of conformational substates of the protein, and a new substate appearing upon membrane binding could be uncovered. Population of this new substate is accompanied by structural reorientations of the G domain, as also indicated by complementary ATR-FTIR and IRRAS measurements. These findings thus illustrate that the membrane controls signaling conformations by acting as an effective interaction partner, which has consequences for the G-domain orientation of membrane-associated N-Ras, which in turn is known to be critical for its effector and modulator interactions. Finally, these results provide insights into the influence of pressure on Ras-controlled signaling events in organisms living under extreme environmental conditions as they are encountered in the deep sea where pressures reach the kbar range.
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 9
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    Genome-wide RNA interference analysis of renal carcinoma survival regulators identifies MCT4 as a Warburg effect metabolic target (2012)
    Wiley-Blackwell
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    Publication Date: 2012-04-17
    Description: Clear cell renal cell carcinoma (ccRCC) is the most common pathological subtype of kidney cancer. Here, we integrated an unbiased genome-wide RNA interference screen for ccRCC survival regulators with an analysis of recurrently over-expressed genes in ccRCC to identify new therapeutic targets in this disease. One of the most potent survival regulators, the monocarboxylate transporter MCT4 (SLC16A3), impaired ccRCC viability in all 8 ccRCC lines tested and was the 7th most over-expressed gene in a meta-analysis of 5 ccRCC expression datasets. MCT4-silencing impaired secretion of lactate generated through glycolysis and induced cell cycle arrest and apoptosis. Silencing MCT4 resulted in intracellular acidosis, and reduction in intracellular ATP production together with partial reversion of the Warburg effect in ccRCC cell lines. Intratumoral heterogeneity in the intensity of MCT4 protein expression was observed in primary ccRCCs. MCT4 protein expression analysis based on the highest intensity of expression in primary ccRCCs was associated with poorer relapse free survival, whereas modal intensity correlated with Fuhrman nuclear grade. Consistent with the potential selection of subclones enriched for MCT4 expression during disease progression, MCT4 expression was greater at sites of metastatic disease. These data suggest that MCT4 may serve as a novel metabolic target to reverse the Warburg effect and limit disease progression in ccRCC. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
    Print ISSN: 0022-3417
    Electronic ISSN: 1096-9896
    Topics: Medicine
    Published by Wiley-Blackwell
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  • 10
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    Flagellin Perception Varies Quantitatively in Arabidopsis thaliana and Its Relatives (2012)
    Oxford University Press
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    Publication Date: 2012-05-16
    Description: Much is known about the evolution of plant immunity components directed against specific pathogen strains: They show pervasive functional variation and have the potential to coevolve with pathogen populations. However, plants are effectively protected against most microbes by generalist immunity components that detect conserved pathogen-associated molecular patterns (PAMPs) and control the onset of PAMP-triggered immunity. In Arabidopsis thaliana , the receptor kinase flagellin sensing 2 (FLS2) confers recognition of bacterial flagellin (flg22) and activates a manifold defense response. To decipher the evolution of this system, we performed functional assays across a large set of A. thaliana genotypes and Brassicaceae relatives. We reveal extensive variation in flg22 perception, most of which results from changes in protein abundance. The observed variation correlates with both the severity of elicited defense responses and bacterial proliferation. We analyzed nucleotide variation segregating at FLS2 in A. thaliana and detected a pattern of variation suggestive of the rapid fixation of a novel adaptive allele. However, our study also shows that evolution at the receptor locus alone does not explain the evolution of flagellin perception; instead, components common to pathways downstream of PAMP perception likely contribute to the observed quantitative variation. Within and among close relatives, PAMP perception evolves quantitatively, which contrasts with the changes in recognition typically associated with the evolution of R genes.
    Print ISSN: 0737-4038
    Electronic ISSN: 1537-1719
    Topics: Biology
    Published by Oxford University Press
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