CiteULike: jyuh's Matthiesen

Loss of the glycine N-methyltransferase gene leads to steatosis and hepatocellular carcinoma in mice.

ML Martínez-Chantar — 2008-05-14T15:55:30-00:00

Hepatology (Baltimore, Md.), Vol. 47, No. 4. (April 2008), pp. 1191-1199.

Glycine N-methyltransferase (GNMT) is the main enzyme responsible for catabolism of excess hepatic S-adenosylmethionine (SAMe). GNMT is absent in hepatocellular carcinoma (HCC), messenger RNA (mRNA) levels are significantly lower in livers of patients at risk of developing HCC, and GNMT has been proposed to be a tumor-susceptibility gene for liver cancer. The identification of several children with liver disease as having mutations of the GNMT gene further suggests that this enzyme plays an important role in liver function. In the current study we studied development of liver pathologies including HCC in GNMT-knockout (GNMT-KO) mice. GNMT-KO mice have elevated serum aminotransferase, methionine, and SAMe levels and develop liver steatosis, fibrosis, and HCC. We found that activation of the Ras and Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathways was increased in liver tumors from GNMT-KO mice coincidently with the suppression of the Ras inhibitors Ras-association domain family/tumor suppressor (RASSF) 1 and 4 and the JAK/STAT inhibitors suppressor of cytokine signaling (SOCS) 1-3 and cytokine-inducible SH2-protein. Finally, we found that methylation of RASSF1 and SOCS2 promoters and the binding of trimethylated lysine 27 in histone 3 to these 2 genes was increased in HCC from GNMT-KO mice. Conclusion: These data demonstrate that loss of GNMT induces aberrant methylation of DNA and histones, resulting in epigenetic modulation of critical carcinogenic pathways in mice.

Annotation-Modules: A tool for finding significant combinations of multisource annotations for gene lists.

Michael Hackenberg — 2008-05-10T08:47:08-00:00

Bioinformatics (Oxford, England) (8 May 2008)

MOTIVATION: The ontological analysis of the gene lists obtained from DNA microarray experiments constitutes an important step in understanding the underlying biology of the analyzed system. Over the last years, many other high-throughput techniques emerged, covering now basically all "omics" fields. However, for some of these techniques the generally used functional ontologies might not be sufficient to describe the biological system represented by the derived gene lists. For a more complete and correct interpretation of these experiments, it is important to extend substantially the number of annotations, adapting the ontological analysis to the new emerging techniques. RESULTS: We developed Annotation-Modules, which offers an improvement over the current tools which improves the current tools in two critical aspects. Firstly, the underlying annotation database implements features from many different fields like gene regulation and expression, sequence properties, evolution and conservation, genomic localization and functional categories - resulting in about 60 different annotation features. Secondly, it examines not only single annotations but also all the combinations, which is important to gain insight into the interplay of different mechanisms in the analyzed biological system. AVAILABILITY: http://web.bioinformatics.cicbiogune.es/AM/AnnotationModules.php.

Control by cholinergic mechanisms.

K Racké — 2008-01-23T03:01:21-00:00

Eur J Pharmacol, Vol. 533, No. 1-3. (8 March 2006), pp. 57-68.

In the respiratory tract acetylcholine is neurotransmitter in ganglia and postganglionic parasympathetic nerves, but in addition is paracrine mediator released from various non-neuronal cells. Almost every cell type present in the respiratory tract expresses nicotinic and muscarinic receptors and therefore appears to be a target for acetylcholine. The present review describes the mechanisms of synthesis and release of acetylcholine from neuronal and non-neuronal cells and the differential control mechanisms. The different cholinoceptors, multiple nicotinic and muscarinic receptors and their signalling are outlined and their involvement in the modulation of the function of various target cells, smooth muscles, nerves, surface epithelial, secretory cells, fibroblasts and inflammatory cells is discussed in detail.

Quantitative proteomic analysis of post-translational modifications of human histones.

HC Beck — 2007-09-26T07:56:37-00:00

Mol Cell Proteomics, Vol. 5, No. 7. (July 2006), pp. 1314-1325.

Histone proteins are subject to a range of post-transcriptional modifications in living cells. The combinatorial nature of these modifications constitutes the "histone code" that dictates chromatin structure and function during development, growth, differentiation, and homeostasis of cells. Deciphering of the histone code is hampered by the lack of analytical methods for monitoring the combinatorial complexity of reversible multisite modifications of histones, including acetylation and methylation. To address this problem, we used LC-MSMS technology and Virtual Expert Mass Spectrometrist software for qualitative and quantitative proteomic analysis of histones extracted from human small cell lung cancer cells. A total of 32 acetylations, methylations, and ubiquitinations were located in the human histones H2A, H2B, H3, and H4, including seven novel modifications. An LC-MSMS-based method was applied in a quantitative proteomic study of the dose-response effect of the histone deacetylase inhibitor (HDACi) PXD101 on histone acetylation in human cell cultures. Triplicate LC-MSMS runs at six different HDACi concentrations demonstrated that PXD101 affects acetylation of histones H2A, H2B, H3, and H4 in a site-specific and dose-dependent manner. This unbiased analysis revealed that a relative increase in acetylated peptide from the histone variants H2A, H2B, and H4 was accompanied by a relative decrease of dimethylated Lys(57) from histone H2B. The dose-response results obtained by quantitative proteomics of histones from HDACi-treated cells were consistent with Western blot analysis of histone acetylation, cytotoxicity, and dose-dependent expression profiles of p21 and cyclin A2. This demonstrates that mass spectrometry-based quantitative proteomic analysis of post-translational modifications is a viable approach for functional analysis of candidate drugs, such as HDAC inhibitors.

Methods, algorithms and tools in computational proteomics: A practical point of view.

R Matthiesen — 2007-09-13T14:17:10-00:00

Proteomics, Vol. 7, No. 16. (August 2007), pp. 2815-2832.

Computational MS-based proteomics is an emerging field arising from the demand of high throughput analysis in numerous large-scale experimental proteomics projects. The review provides a broad overview of a number of computational tools available for data analysis of MS-based proteomics data and gives appropriate literature references to detailed description of algorithms. The review provides, to some extent, discussion of algorithms and methods for peptide and protein identification using MS data, quantitative proteomics, and data storage. The hope is that it will stimulate discussion and further development in computational proteomics. Computational proteomics deserves more scientific attention. There are far fewer computational tools and methods available for proteomics compared to the number of microarray tools, despite the fact that data analysis in proteomics is much more complex than microarray analysis.

Integration of gel-based proteome data with pProRep.

K Laukens — 2007-08-26T13:09:05-00:00

Bioinformatics, Vol. 22, No. 22. (15 November 2006), pp. 2838-2840.

pProRep is a web application integrating electrophoretic and mass spectral data from proteome analyses into a relational database. The graphical web-interface allows users to upload, analyse and share experimental proteome data. It offers researchers the possibility to query all previously analysed datasets and can visualize selected features, such as the presence of a certain set of ions in a peptide mass spectrum, on the level of the two-dimensional gel. AVAILABILITY: The pProRep package and instructions for its use can be downloaded from http://www.ptools.ua.ac.be/pProRep. The application requires a web server that runs PHP 5 (http://www.php.net) and MySQL. Some (non-essential) extensions need additional freely available libraries: details are described in the installation instructions.