Alternative splicing microarrays reveal functional expression of neuron-specific regulators in Hodgkin lymphoma cells.
ABSTRACT Alternative splicing provides a versatile mechanism of gene regulation, which is often subverted in disease. We have used customized oligonucleotide microarrays to interrogate simultaneously the levels of expression of splicing factors and the patterns of alternative splicing of genes involved in tumor progression. Analysis of RNAs isolated from cell lines derived from Hodgkin lymphoma tumors indicate that the relative abundance of alternatively spliced isoforms correlates with transformation and tumor grade. Changes in expression of regulators were also detected, and a subset sample was confirmed at the protein level. Ectopic expression of neuron-specific splicing regulatory proteins of the Nova family was observed in some cell lines and tumor samples, correlating with expression of a neuron-specific mRNA isoform of JNK2 kinase. This microarray design can help assess the role of alternative splicing in a variety of biological and medical problems and potentially serve as a diagnostic tool.
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ABSTRACT: Prior to the completion of the human genome project, the human genome was thought to have a greater number of genes as it seemed structurally and functionally more complex than other simpler organisms. This along with the belief of "one gene, one protein", were demonstrated to be incorrect. The inequality in the ratio of gene to protein formation gave rise to the theory of alternative splicing (AS). AS is a mechanism by which one gene gives rise to multiple protein products. Numerous databases and online bioinformatic tools are available for the detection and analysis of AS. Bioinformatics provides an important approach to study mRNA and protein diversity by various tools such as expressed sequence tag (EST) sequences obtained from completely processed mRNA. Microarrays and deep sequencing approaches also aid in the detection of splicing events. Initially it was postulated that AS occurred only in about 5% of all genes but was later found to be more abundant. Using bioinformatic approaches, the level of AS in human genes was found to be fairly high with 35-59% of genes having at least one AS form. Our ability to determine and predict AS is important as disorders in splicing patterns may lead to abnormal splice variants resulting in genetic diseases. In addition, the diversity of proteins produced by AS poses a challenge for successful drug discovery and therefore a greater understanding of AS would be beneficial.Current Genomics 05/2013; 14(3):182-94. · 2.48 Impact Factor
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ABSTRACT: Systematic genetic and epigenetic alterations occurring in almost all cancer cells result in the ectopic expression of a variety of tissue-specific potent regulatory factors. This review sheds light on a new aspect of cancer based on the integration of the 'out of context' activity of tissue-restricted genes into the biology of cancer cells. A systematic screen for the ectopic activation of tissue-restricted genes in a variety of cancers has revealed that many normally silent genes are expressed in tumours of all origins. This aberrant gene activation not only could be used as a source of biomarkers, but also, in several cases, reveals clear oncogenic mechanisms associated with the corresponding ectopically expressed factors. The characteristic of all cancer cells, which systematically reprogram tissue-specific gene expression and activate silent genes, can be exploited to develop new anticancer strategies aiming at the detection of malignant states, the prediction of their evolution and drug sensitivity and the discovery of new therapeutic approaches.Current opinion in oncology 11/2013; · 4.09 Impact Factor
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ABSTRACT: The accurate expression of the genetic information is regulated by processes like mRNA splicing, proposed after the discoveries of Phil Sharp and Richard Roberts, who demonstrated the existence of intronic sequences, present in almost every structural eukaryotic gene, which should be precisely removed. This intron removal is called "splicing", which generates different proteins from a single mRNA, with different or even antagonistic functions. We currently know that alternative splicing is the most important source of protein diversity, given that 70% of the human genes undergo splicing and that mutations causing defects in this process could originate up to 50% of genetic diseases, including cancer. When these defects occur in genes involved in cell adhesion, proliferation and cell cycle regulation, there is an impact on cancer progression, rising the opportunity to diagnose and treat some types of cancer according to a particular splicing profile.Medicina Clínica 04/2014; · 1.40 Impact Factor