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Individual Genes (individual + gene)
Selected AbstractsGlobal transmission/disequilibrium tests based on haplotype sharing in multiple candidate genesGENETIC EPIDEMIOLOGY, Issue 4 2005Kai Yu Abstract It is well recognized that multiple genes are likely contributing to the susceptibility of most common complex diseases. Studying one gene at a time might reduce our chance to identify disease susceptibility genes with relatively small effect sizes. Therefore, it is crucial to develop statistical methods that can assess the effect of multiple genes collectively. Motivated by the increasingly available high-density markers across the whole human genome, we propose a class of TDT-type methods that can jointly analyze haplotypes from multiple candidate genes (linked or unlinked). Our approach first uses a linear signed rank statistic to compare at an individual gene level the structural similarity among transmitted haplotypes against that among non-transmitted haplotypes. The results of the ranked comparisons from all considered genes are subsequently combined into global statistics, which can simultaneously test the association of the set of genes with the disease. Using simulation studies, we find that the proposed tests yield correct type I error rates in stratified populations. Compared with the gene-by-gene test, the new global tests appear to be more powerful in situations where all candidate genes are associated with the disease. Genet. Epidemiol. 2005. © 2005 Wiley-Liss, Inc. [source] Identification of a new genotype H wild-type mumps virus strain and its molecular relatedness to other virulent and attenuated strainsJOURNAL OF MEDICAL VIROLOGY, Issue 2 2003Georgios Amexis Abstract A single clinical isolate of mumps virus designated 88-1961 was obtained from a patient hospitalized with a clinical history of upper respiratory tract infection, parotitis, severe headache, fever and lymphadenopathy. We have sequenced the full-length genome of 88-1961 and compared it against all available full-length sequences of mumps virus. Based upon its nucleotide sequence of the SH gene 88-1961 was identified as a genotype H mumps strain. The overall extent of nucleotide and amino acid differences between each individual gene and protein of 88-1961 and the full-length mumps samples showed that the missense to silent ratios were unevenly distributed. Upon evaluation of the consensus sequence of 88-1961, four positions were found to be clearly heterogeneous at the nucleotide level (NP 315C/T, NP 318C/T, F 271A/C, and HN 855C/T). Sequence analysis revealed that the amino acid sequences for the NP, M, and the L protein were the most conserved, whereas the SH protein exhibited the highest variability among the compared mumps genotypes A, B, and G. No identifying molecular patterns in the non-coding (intergenic) or coding regions of 88-1961 were found when we compared it against relatively virulent (Urabe AM9 B, Glouc1/UK96, 87-1004 and 87-1005) and non-virulent mumps strains (Jeryl Lynn and all Urabe Am9 A substrains). J. Med. Virol. 70: 284,286, 2003. © 2003 Wiley-Liss, Inc. [source] Optimization of an siRNA-expression system with an improved hairpin and its significant suppressive effects in mammalian cellsTHE JOURNAL OF GENE MEDICINE, Issue 7 2004Makoto Miyagishi Abstract Background RNA interference (RNAi) is a phenomenon in which expression of an individual gene can be specifically silenced by introducing a double-stranded RNA, one complementary to the gene, into cells. This phenomenon can be observed in mammalian cells when small interfering RNAs (siRNAs) are used, and is receiving attention as the most powerful tool for reverse genetics in the post genome era. Several groups have developed vector-based siRNA-expression systems that can induce RNAi in living cells. Methods We describe here a comparative analysis of various siRNA-expression systems, in which we examined the effects of stem length, loop sequence and insertion of mutation(s) and/or bulges in the stem sequence on silencing effects and on the stability of the vectors. Results As a result of the comparative analysis, we determined the following optimized siRNA-expression system: U6 promoter-driven hairpin-type dsRNA with 21-nt stem length, three to four mutations in the sense strand only, and the optimized 9-nt loop sequence, derived from microRNA. Moreover, we demonstrate that the siRNA-expression system with a tetracycline-regulated U6 promoter(s) could have the potential to control RNAi in cells, and that the HIV vector-mediated transfer of an siRNA-expression cassette into cells resulted in efficient silencing of a target gene at a multiplicity of infection as low as five. Conclusion The mutated hairpin siRNAs and their genetically stable coding vectors could be very useful for gene knockdown experiments, and could further benefit gene therapy using RNAi. Copyright © 2004 John Wiley & Sons, Ltd. [source] Improved Detection of Differentially Expressed Genes Through Incorporation of Gene LocationsBIOMETRICS, Issue 3 2009Guanghua Xiao Summary In determining differential expression in cDNA microarray experiments, the expression level of an individual gene is usually assumed to be independent of the expression levels of other genes, but many recent studies have shown that a gene's expression level tends to be similar to that of its neighbors on a chromosome, and differentially expressed (DE) genes are likely to form clusters of similar transcriptional activity along the chromosome. When modeled as a one-dimensional spatial series, the expression level of genes on the same chromosome frequently exhibit significant spatial correlation, reflecting spatial patterns in transcription. By modeling these spatial correlations, we can obtain improved estimates of transcript levels. Here, we demonstrate the existence of spatial correlations in transcriptional activity in the,Escherichia coli,(E. coli) chromosome across more than 50 experimental conditions. Based on this finding, we propose a hierarchical Bayesian model that borrows information from neighboring genes to improve the estimation of the expression level of a given gene and hence the detection of DE genes. Furthermore, we extend the model to account for the circular structure of,E. coli,chromosome and the intergenetic distance between gene neighbors. The simulation studies and analysis of real data examples in,E. coli,and yeast,Saccharomyces cerevisiae,show that the proposed method outperforms the commonly used significant analysis of microarray (SAM),t -statistic in detecting DE genes. [source] Prokaryotic genome regulation: multifactor promoters, multitarget regulators and hierarchic networksFEMS MICROBIOLOGY REVIEWS, Issue 5 2010Akira Ishihama Abstract The vast majority of experimental data have been accumulated on the transcription regulation of individual genes within a single model prokaryote, Escherichia coli, which form the well-established on,off switch model of transcription by DNA-binding regulatory proteins. After the development of modern high-throughput experimental systems such as microarray analysis of whole genome transcription and the Genomic SELEX search for the whole set of regulation targets by transcription factors, a number of E. coli promoters are now recognized to be under the control of multiple transcription factors, as in the case of eukaryotes. The number of regulation targets of a single transcription factor has also been found to be more than hitherto recognized, ranging up to hundreds of promoters, genes or operons for several global regulators. The multifactor promoters and the multitarget transcription factors can be assembled into complex networks of transcription regulation, forming hierarchical networks. [source] Cholesterol homeostasis markers are localized to mouse hippocampal pyramidal and granule layersHIPPOCAMPUS, Issue 8 2010Chris M. Valdez Abstract Changes in brain cholesterol homeostasis are associated with multiple diseases, such as Alzheimer's and Huntington's; however, controversy persists as to whether adult neurons produce their own cholesterol, or if it is outsourced to astrocytes. To address this issue, we analyzed 25 genes most immediately involved in cholesterol homeostasis from in situ data provided by the Allen Brain Mouse Atlas. We compared the relative mRNA expression in the pyramidal and granule layers, populated with neurons, with the rest of the hippocampus which is populated with neuronal processes and glia. Comparing the expression of the individual genes to markers for neurons and astrocytes, we found that cholesterol homeostasis genes are preferentially targeted to neuronal layers. Therefore, changes in gene expression levels might affect neuronal populations directly. © 2010 Wiley-Liss, Inc. [source] Epigenetics of prostate cancer: beyond DNA methylationJOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 1 2006W. A. Schulz Abstract Epigenetic mechanisms permit the stable inheritance of cellular properties without changes in DNA sequence or amount. In prostate carcinoma, epigenetic mechanisms are essential for development and progression, complementing, amplifying and diversifying genetic alterations. DNA hypermethylation affects at least 30 individual genes, while repetitive sequences including retrotransposons and selected genes become hypomethylated. Hypermethylation of several genes occurs in a coordinate manner early in carcinogenesis and can be exploited for cancer detection, whereas hypomethylation and further hypermethylation events are associated with progression. DNA methylation alterations interact with changes in chromatin proteins. Prominent alterations at this level include altered patterns of histone modification, increased expression of the EZH2 polycomb histone methyltransferase, and changes in transcriptional corepressors and coactivators. These changes may make prostate carcinoma particularly susceptible to drugs targeting chromatin and DNA modifications. They relate to crucial alterations in a network of transcription factors comprising ETS family proteins, the androgen receptor, NKX3.1, KLF, and HOXB13 homeobox proteins. This network controls differentiation and proliferation of prostate epithelial cells integrating signals from hormones, growth factors and cell adhesion proteins that are likewise distorted in prostate cancer. As a consequence, prostate carcinoma cells appear to be locked into an aberrant state, characterized by continued proliferation of largely differentiated cells. Accordingly, stem cell characteristics of prostate cancer cells appear to be secondarily acquired. The aberrant differentiation state of prostate carcinoma cells also results in distorted mutual interactions between epithelial and stromal cells in the tumor that promote tumor growth, invasion, and metastasis. [source] Differential gene expression analysis using paraffin-embedded tissues after laser microdissectionJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 5 2003Joung-Ok Kim Abstract Recent advances in laser microdissection allow for precise removal of pure cell populations from morphologically preserved tissue sections. However, RNA from paraffin-embedded samples is usually degraded during microdissection. The purpose of this study is to determine the optimal fixative for RNA extractions from laser microdissected paraffin-embedded samples. The integrity of RNA was evaluated with the intactness of 18S and 28S ribosomal RNA by electrophoresis and by the length of individual gene transcripts using RT-PCR. The various fixatives were methacarn (a combination of methanol, chloroform, and acetic acid) and several concentrations of ethanol and isopropanol. Methacarn was the optimal fixative for RNA preservation in paraffin-embedded tissues, which included liver, lung, kidney, muscle, and limb. Based on RT-PCR analysis, methacarn fixed samples exhibited the expected RNA sizes for individual genes such as glyceraldehyde-3-phosphate-dehydrogenase (GAPDH) and bone-related genes (e.g., alkaline phosphatase and osteonectin). The laser microdissection technique with methacarn fixation was then applied to analyze the differential gene expression between hypertrophic and proliferative chondrocytes in the growth plate of long bone. The expression of type X collagen (ColX,1), a specific gene for hypertrophic chondrocytes, was only observed in hypertrophic chondrocytes, while type II collagen (Col2,1) was observed more broadly in the growth plate as anticipated. Thus, combining laser microdissection with methacarn fixation facilitates the examination of differentially expressed genes from various tissues. © 2003 Wiley-Liss, Inc. [source] Developmental control via GATA factor interplay at chromatin domainsJOURNAL OF CELLULAR PHYSIOLOGY, Issue 1 2005Emery H. Bresnick Despite the extraordinary task of packaging mammalian DNA within the constraints of a cell nucleus, individual genes assemble into cell type-specific chromatin structures with high fidelity. This chromatin architecture is a crucial determinant of gene expression signatures that distinguish specific cell types. Whereas extensive progress has been made on defining biochemical and molecular mechanisms of chromatin modification and remodeling, many questions remain unanswered about how cell type-specific chromatin domains assemble and are regulated. This mini-review will discuss emerging studies on how interplay among members of the GATA family of transcription factors establishes and regulates chromatin domains. Dissecting mechanisms underlying the function of hematopoietic GATA factors has revealed fundamental insights into the control of blood cell development from hematopoietic stem cells and the etiology of pathological states in which hematopoiesis is perturbed. © 2005 Wiley-Liss, Inc. [source] Calorie restriction effects on silencing and recombination at the yeast rDNAAGING CELL, Issue 6 2009Daniel L. Smith Jr Summary Aging research has developed rapidly over the past decade, identifying individual genes and molecular mechanisms of the aging process through the use of model organisms and high throughput technologies. Calorie restriction (CR) is the most widely researched environmental manipulation that extends lifespan. Activation of the NAD+ -dependent protein deacetylase Sir2 (Silent Information Regulator 2) has been proposed to mediate the beneficial effects of CR in the budding yeast Saccharomyces cerevisiae, as well as other organisms. Here, we show that in contrast to previous reports, Sir2 is not stimulated by CR to strengthen silencing of multiple reporter genes in the rDNA of S. cerevisiae. CR does modestly reduce the frequency of rDNA recombination, although in a SIR2 -independent manner. CR-mediated repression of rDNA recombination also does not correlate with the silencing of Pol II-transcribed noncoding RNAs derived from the rDNA intergenic spacer, suggesting that additional silencing-independent pathways function in lifespan regulation. [source] A population genomic approach to map recent positive selection in model speciesMOLECULAR ECOLOGY, Issue 16 2008P. PAVLIDIS Abstract Based on nearly complete genome sequences from a variety of organisms data on naturally occurring genetic variation on the scale of hundreds of loci to entire genomes have been collected in recent years. In parallel, new statistical tests have been developed to infer evidence of recent positive selection from these data and to localize the target regions of selection in the genome. These methods have now been successfully applied to Drosophila melanogaster, humans, mice and a few plant species. In genomic regions of normal recombination rates, the targets of positive selection have been mapped down to the level of individual genes. [source] Optimization of pathogenicity assays to study the Arabidopsis thaliana,Xanthomonas campestris pv. campestris pathosystemMOLECULAR PLANT PATHOLOGY, Issue 3 2005DAMIEN MEYER SUMMARY The cruciferous weed Arabidopsis thaliana and the causal agent of black rot disease of Crucifers Xanthomonas campestris pv. campestris (Xcc) are both model organisms in plant pathology. Their interaction has been studied successfully in the past, but these investigations suffered from high variability. In the present study, we describe an improved Arabidopsis,Xcc pathosystem that is based on a wound inoculation procedure. We show that after wound inoculation, Xcc colonizes the vascular system of Arabidopsis leaves and causes typical black rot symptoms in a compatible interaction, while in an incompatible interaction bacterial multiplication is inhibited. The highly synchronous and reproducible symptom expression allowed the development of a disease scoring scheme that enabled us to analyse the effects of mutations in individual genes on plant resistance or on bacterial virulence in a simple and precise manner. This optimized Arabidopsis,Xcc pathosystem will be a robust tool for further genetic and post-genomic investigation of fundamental questions in plant pathology. [source] Animal models of Williams syndrome,AMERICAN JOURNAL OF MEDICAL GENETICS, Issue 2 2010Lucy R. Osborne Abstract In recent years, researchers have generated a variety of mouse models in an attempt to dissect the contribution of individual genes to the complex phenotype associated with Williams syndrome (WS). The mouse genome is easily manipulated to produce animals that are copies of humans with genetic conditions, be it with null mutations, hypomorphic mutations, point mutations, or even large deletions encompassing many genes. The existing mouse models certainly seem to implicate hemizygosity for ELN, BAZ1B, CLIP2, and GTF2IRD1 in WS, and new mice with large deletions of the WS region are helping us to understand both the additive and potential combinatorial effects of hemizygosity for specific genes. However, not all genes that are haploinsufficient in humans prove to be so in mice and the effect of genetic background can also have a significant effect on the penetrance of many phenotypes. Thus although mouse models are powerful tools, the information garnered from their study must be carefully interpreted. Nevertheless, mouse models look set to provide a wealth of information about the neuroanatomy, neurophysiology and molecular pathways that underlie WS and in the future will act as essential tools for the development and testing of therapeutics. © 2010 Wiley-Liss, Inc. [source] Comparative analysis of gene expression on mRNA and protein level during development of Streptomyces cultures by using singular value decompositionPROTEINS: STRUCTURE, FUNCTION AND BIOINFORMATICS, Issue 21 2007Jiri Vohradsky Dr. Abstract This paper describes a comparative systems level analysis of the developmental proteome and transcriptome in the model antibiotic-producing eubacterium Streptomyces coelicolor, cultured on different media. The analysis formulates expression as the superposition of effects of regulatory networks and biological processes which can be identified using singular value decomposition (SVD) of a data matrix formed by time series measurements of expression of individual genes throughout the cell cycle of the bacterium. SVD produces linearly orthogonal factors, each of which can represent an independent system behavior defined by a linear combination of the genes/proteins highly correlated with the corresponding factor. By using SVD of the developmental time series of gene expression, as measured by both protein and RNA levels, we show that on the highest level of control (representing the basic kinetic behavior of the population), the results are identical, regardless of the type of experiment or cultivation method. The results show that this approach is capable of identifying basic regulatory processes independent of the environment in which the organism lives. It also shows that these processes are manifested equally on protein and RNA levels. Biological interpretation of the correlation of the genes and proteins with significant eigenprofiles (representing the highest level kinetic behavior of protein and/or RNA synthesis) revealed their association with metabolic processes, stress responses, starvation, and secondary metabolite production. [source] Identification of genetic markers associated with fatness and leg weakness traits in the pigANIMAL GENETICS, Issue 6 2009B. Fan Summary Pigs have undergone long-term selection in commercial conditions for improved rate and efficiency of lean gain. Interestingly, it has been observed in both experimental and field conditions that leg weakness has increased over time, concurrent with the selection for improved rate of lean gain, while fatter animals tend to have better leg action, and foot and leg (FL) structure. The exact molecular mechanisms or individual genes responsible for this apparent genetic correlation between fatness and leg weakness and other physical adaptability traits have been less well reported. Based on our recent studies involving candidate genes and leg weakness traits, the present investigation has identified 30 SNPs from 26 genes that were found to be associated with 10th rib backfat in a sow population consisting of 2066 animals. The specific alleles associated with increased backfat tended to be associated with better overall leg action, as shown for the genes including MTHFR, WNT2, APOE, BMP8, GNRHR and OXTR, while inconsistent associations with the single FL structure trait and backfat were observed for other genes. This study suggests that in some cases there may be a common genetic mechanism or linked genes regulating fatness and leg weakness. Such relationships are clearly complex, and the utilization of genetic markers associated with both traits should be treated cautiously. [source] The genome-centric concept: resynthesis of evolutionary theoryBIOESSAYS, Issue 5 2009Henry H. Q. Heng Abstract Modern biology has been heavily influenced by the gene-centric concept. Paradoxically, this very concept , on which bioresearch is based , is challenged by the success of gene-based research in terms of explaining evolutionary theory. To overcome this major roadblock, it is essential to establish new theories, to not only solve the key puzzles presented by the gene-centric concept, but also to provide a conceptual framework that allows the field to grow. This paper discusses a number of paradoxes and illustrates how they can be addressed by the genome-centric concept in order to further resynthesize evolutionary theory. In particular, methodological breakthroughs that analyze genome evolution are discussed. The multiple interactions among different levels of a complex system provide the key to understanding the relationship between self-organization and natural selection. Darwinian natural selection applies to the biological level due to its unique genetic and heterogeneous features, but does not simply or directly apply to either the lower non-living level or higher intellectual society level. At the complex bio-system level, the genome context (the entire package of genes and their genomic physical relationship or genomic topology), not the individual genes, defines the system and serves as the principle selection platform for evolution. [source] Predicting phenotypic effects of gene perturbations in C. elegans using an integrated network modelBIOESSAYS, Issue 8 2008Karsten Borgwardt Predicting the phenotype of an organism from its genotype is a central question in genetics. Most importantly, we would like to find out if the perturbation of a single gene may be the cause of a disease. However, our current ability to predict the phenotypic effects of perturbations of individual genes is limited. Network models of genes are one tool for tackling this problem. In a recent study, (Lee et al.) it has been shown that network models covering the majority of genes of an organism can be used for accurately predicting phenotypic effects of gene perturbations in multicellular organisms. BioEssays 30:707,710, 2008. © 2008 Wiley Periodicals, Inc. [source] Gene expression in actinic keratoses: pharmacological modulation by imiquimodBRITISH JOURNAL OF DERMATOLOGY, Issue 6 2004B. Lysa Summary Background, Actinic keratoses (AKs) are premalignant lesions that can progress into squamous cell carcinoma. Imiquimod, which belongs to the new class of immune-response modifiers, was recently shown to be effective in the treatment of AKs. The underlying mechanisms are not fully understood. Objectives, To study the expression of individual genes in uninvolved skin and AKs before therapy and to elucidate the way in which the expression of these genes is influenced by imiquimod therapy. Methods, We treated 13 patients with AK with imiquimod and compared gene expression before, during (five patients) and after (eight patients) therapy with that in uninvolved skin. We analysed genes coding for inflammatory cytokines or their receptors, adhesion molecules, anti-apoptotic proteins, p53 and toll-like receptors (TLRs) by reverse-transcriptase polymerase chain reaction. Results, Comparing uninvolved skin and untreated AK, we found significant differences in the expression of interleukin (IL)-6, hurpin, TLR7 and TLR8. During imiquimod therapy, we detected a further upregulation of interferon-,, IL-6, IL-10 receptor 1 and TLR7. In contrast, two anti-apoptotic genes, hurpin and HAX-1, were downregulated. We did not detect significant differences in gene expression for p53, tumour necrosis factor-, and ,- and ,-catenins. Clinically, the upregulated expression of the proinflammatory cytokines correlated with the local inflammation induced by imiquimod. Conclusions, Our results indicate that specific differences in gene expression are detectable between AK and uninvolved skin. Imiquimod influenced the expression of most genes analysed in this study. This work extends previous findings on the effects of imiquimod on gene regulation in AKs. [source] "Natural restoration" can generate biological complexityCOMPLEXITY, Issue 2 2005Emile ZuckerkandlArticle first published online: 16 DEC 200 Abstract Factor complexes engaged in transcriptional regulation of gene expression and their cognate DNA elements recurrently suffer mutational damage that can result in deadaptations in the mutual fit of interacting macromolecules. Such mutations can spread in populations by drift if their functional consequences are not severe. Mutational restorations of the damaged complexes may ensue and can take many forms. One of these forms would represent spontaneous increases in gene interaction complexity and correlated aspects of organismic complexity. In this particular mode of restoration, restabilization of a factor/factor/DNA complex occurs through the binding of an additional factor. Factors added under such circumstances to regulatory kits of individual genes are thought to be at the origin of a slow but persistent "complexity drive." This drive seems to be resisted in many forms whose developmental outcome has reached a finish line difficult to pass, but imposes itself along other lines of phylogenetic descent. In the process of restoration by an additional factor, the chances are significant that the original regulatory control of a target gene is not recovered exactly and that the restored gene expression has novel spatial, temporal, or quantitative characteristics. These new characteristics, which represent a functional transfer of the gene to a new domain of activity, may be selectable, even when the physicochemical properties of the gene product have remained largely unchanged. As a consequence of such activity transfers under quasi-constancy of the molecular properties of the protein encoded by the regulation's target gene, the activity domain originally covered by that target gene may be left at least in part functionally vacant. At that point, an unmodified duplicate of the target gene and of its original regulatory dependencies probably becomes in turn selectable. A causal link is therefore predicted between the regulatory specialization and selection of one of two duplicates and the regulatory maintenance and selection of the other. A conserved increase in gene number would result indirectly from the regulatory shift in paralogs, and the organism's complexity would be increased in this sense also, complexity as number of genes in addition to complexity as number of regulatory factors per gene. It is thus proposed that increased biological complexity, innovation in the gene regulatory network, and the development of a novel evolutionary potential can be the result, counterintuitively, of conservative forces that intervene when mutations play a survivable form of havoc with the system of gene regulation. Increasing complexity, then, could be seen as one of the side effects of "natural restoration." This phrase designates the mutational re-establishment in the gene whose regulation has been damaged of a functionally effective activity pattern, albeit, perhaps, with changes in its mode of expression in regard to location, time, and rate. The higher complexity, innovation in the gene regulatory network, of higher organisms,their very character of higher organisms,would to a significant extent be a side effect of episodes of natural selection aimed at functional restoration, not at complexity itself. Regulatory impairment, the point of departure of the process outlined, represents a controller gene disease. It thus may well be the case that molecular diseases, the effects on the individual of inheritable structural decay, are among the conditions of the evolution of higher organisms. © 2005 Wiley Periodicals, Inc. Complexity 11: 14,27, 2005 [source] Gene expression analysis of BCR/ABL1-dependent transcriptional response reveals enrichment for genes involved in negative feedback regulationGENES, CHROMOSOMES AND CANCER, Issue 4 2008Petra Håkansson Philadelphia (Ph) chromosome-positive leukemia is characterized by the BCR/ABL1 fusion protein that affects a wide range of signal transduction pathways. The knowledge about its downstream target genes is, however, still quite limited. To identify novel BCR/ABL1-regulated genes we used global gene expression profiling of several Ph-positive and Ph-negative cell lines treated with imatinib. Following imatinib treatment, the Ph-positive cells showed decreased growth, viability, and reduced phosphorylation of BCR/ABL1 and STAT5. In total, 142 genes were identified as being dependent on BCR/ABL1-mediated signaling, mainly including genes involved in signal transduction, e.g. the JAK/STAT, MAPK, TGFB, and insulin signaling pathways, and in regulation of metabolism. Interestingly, BCR/ABL1 was found to activate several genes involved in negative feedback regulation (CISH, SOCS2, SOCS3, PIM1, DUSP6, and TNFAIP3), which may act to indirectly suppress the tumor promoting effects exerted by BCR/ABL1. In addition, several genes identified as deregulated upon BCR/ABL1 expression could be assigned to the TGFB and NFkB signaling pathways, as well as to reflect the metabolic adjustments needed for rapidly growing cells. Apart from providing important pathogenetic insights into BCR/ABL1 -mediated leukemogenesis, the present study also provides a number of pathways/individual genes that may provide attractive targets for future development of targeted therapies. This article contains Supplementary Material available at http://www.interscience.wiley.com/jpages/1045,2257/suppmat. © 2008 Wiley-Liss, Inc. [source] | ||||||||||||||||