The FUSE binding proteins FBP1 and FBP3 are potential c-myc regulators in renal, but not in prostate and bladder cancer

BACKGROUND: The three far-upstream element (FUSE) binding proteins (FBP1, FBP2, and FBP3) belong to an ancient family of single-stranded DNA binding proteins which are required for proper regulation of the c-myc proto-oncogene. Whereas it is known that c-myc alterations play a completely different role in various carcinomas of the urogenital tract, the relevance of FBPs is unclear. Methods: FBP1, FBP3 and c-myc expression was studied in 105 renal cell, 95 prostate and 112 urinary bladder carcinomas by immunohistochemistry using tissue microarrays. High rates of FBP1 and FBP3 expression were observed in all cancer types. RESULTS: There was a concomitant up-regulation of FBP1 and FBP3 in renal cell and prostate carcinomas (p<0.001 both). C-myc expression was detectable in 21% of prostate, 30% of renal and 34% of urothelial carcinomas. Interestingly, strong FBP1 and FBP3 expression was associated with c-myc up-regulation in clear cell renal cell carcinomas (p<0.001 and 0.05 resp.), but not in bladder or prostate cancer. CONCLUSIONS: The correlation between FBP1/FBP3, c-myc and high proliferation rate in renal cell carcinoma provides strong in vivo support for the suggested role of FBP1 and FBP3 as activators of c-myc. The frequent up-regulation of FBP1 and FBP3 in urothelial and prostate carcinoma suggests that FBPs also have an important function in gene regulation of these tumors

Challenges of molecular nutrition research 6: the nutritional phenotype database to store, share and evaluate nutritional systems biology studies

The challenge of modern nutrition and health research is to identify food-based strategies promoting life-long optimal health and well-being. This research is complex because it exploits a multitude of bioactive compounds acting on an extensive network of interacting processes. Whereas nutrition research can profit enormously from the revolution in ‘omics’ technologies, it has discipline-specific requirements for analytical and bioinformatic procedures. In addition to measurements of the parameters of interest (measures of health), extensive description of the subjects of study and foods or diets consumed is central for describing the nutritional phenotype. We propose and pursue an infrastructural activity of constructing the “Nutritional Phenotype database” (dbNP). When fully developed, dbNP will be a research and collaboration tool and a publicly available data and knowledge repository. Creation and implementation of the dbNP will maximize benefits to the research community by enabling integration and interrogation of data from multiple studies, from different research groups, different countries and different—omics levels. The dbNP is designed to facilitate storage of biologically relevant, pre-processed—omics data, as well as study descriptive and study participant phenotype data. It is also important to enable the combination of this information at different levels (e.g. to facilitate linkage of data describing participant phenotype, genotype and food intake with information on study design and—omics measurements, and to combine all of this with existing knowledge). The biological information stored in the database (i.e. genetics, transcriptomics, proteomics, biomarkers, metabolomics, functional assays, food intake and food composition) is tailored to nutrition research and embedded in an environment of standard procedures and protocols, annotations, modular data-basing, networking and integrated bioinformatics. The dbNP is an evolving enterprise, which is only sustainable if it is accepted and adopted by the wider nutrition and health research community as an open source, pre-competitive and publicly available resource where many partners both can contribute and profit from its developments. We introduce the Nutrigenomics Organisation (NuGO, http://www.nugo.org) as a membership association responsible for establishing and curating the dbNP. Within NuGO, all efforts related to dbNP (i.e. usage, coordination, integration, facilitation and maintenance) will be directed towards a sustainable and federated infrastructure

Single neuron transcriptomics identify SRSF/ SR protein B52 as a regulator of axon growth and Choline acetyltransferase splicing.

We removed single identified neurons from living Drosophila embryos to gain insight into the transcriptional control of developing neuronal networks. The microarray analysis of the transcriptome of two sibling neurons revealed seven differentially expressed transcripts between both neurons (threshold: log(2)1.4). One transcript encodes the RNA splicing factor B52. Loss of B52 increases growth of axon branches. B52 function is also required for Choline acetyltransferase (ChAT ) splicing. At the end of embryogenesis, loss of B52 function impedes splicing of ChAT, reduces acetylcholine synthesis, and extends the period of uncoordinated muscle twitches during larval hatching. ChAT regulation by SRSF proteins may be a conserved feature since changes in SRSF5 expression and increased acetylcholine levels in brains of bipolar disease patients have been reported recently

Eye Development under the control of SRp55/B52-Mediated Alternative Splicing of eyeless

The genetic programs specifying eye development are highly conserved during evolution and involve the vertebrate Pax-6 gene and its Drosophila melanogaster homolog eyeless (ey). Here we report that the SR protein B52/SRp55 controls a novel developmentally regulated splicing event of eyeless that is crucial for eye growth and specification in Drosophila. B52/SRp55 generates two isoforms of eyeless differing by an alternative exon encoding a 60-amino-acid insert at the beginning of the paired domain. The long isoform has impaired ability to trigger formation of ectopic eyes and to bind efficiently Eyeless target DNA sequences in vitro. When over-produced in the eye imaginal disc, this isoform induces a small eye phenotype, whereas the isoform lacking the alternative exon triggers eye over-growth and strong disorganization. Our results suggest that B52/SRp55 splicing activity is used during normal eye development to control eye organogenesis and size through regulation of eyeless alternative splicing

The SR Protein B52/SRp55 Is Required for DNA Topoisomerase I Recruitment to Chromatin, mRNA Release and Transcription Shutdown

DNA- and RNA-processing pathways are integrated and interconnected in the eukaryotic nucleus to allow efficient gene expression and to maintain genomic stability. The recruitment of DNA Topoisomerase I (Topo I), an enzyme controlling DNA supercoiling and acting as a specific kinase for the SR-protein family of splicing factors, to highly transcribed loci represents a mechanism by which transcription and processing can be coordinated and genomic instability avoided. Here we show that Drosophila Topo I associates with and phosphorylates the SR protein B52. Surprisingly, expression of a high-affinity binding site for B52 in transgenic flies restricted localization, not only of B52, but also of Topo I to this single transcription site, whereas B52 RNAi knockdown induced mis-localization of Topo I in the nucleolus. Impaired delivery of Topo I to a heat shock gene caused retention of the mRNA at its site of transcription and delayed gene deactivation after heat shock. Our data show that B52 delivers Topo I to RNA polymerase II-active chromatin loci and provide the first evidence that DNA topology and mRNA release can be coordinated to control gene expression

SS18 Together with Animal-Specific Factors Defines Human BAF-Type SWI/SNF Complexes

Contains fulltext : 94049.pdf (publisher's version ) (Open Access

Covariant density functional theory for exotic nuclei near the neutron drip-line

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