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PubMed2004

Application of bioinformatics in cancer epigenetics.

With the completion of the human genome sequence and the advent of high-throughput genomics-based technologies, it is now possible to study the entire human genome and epigenome. The challenge in the next decade of biomedical research is to functionally annotate the genome, epigenome, transcriptome, and proteome. High-throughput genome technology has already produced massive amounts of data including genome sequences, single nucleotide polymorphisms, and microarray gene expression. Our ability to manage and analyze data needs to match the speed of data acquisition. We will summarize our studies of allele-specific gene expression using genomic and computational approaches and identification of sequence motifs that are signature of imprinted genes. We will also discuss about how bioinformatics can facilitate epigenetic researches.

Computational Biology↗
PubMed2006

Molecular genetic studies of gene identification for osteoporosis: a 2004 update.

This review summarizes comprehensively the most important and representative molecular genetics studies of gene identification for osteoporosis published up to the end of December 2004. It is intended to constitute a sequential update of our previously published review covering the available data up to the end of 2002. Evidence from candidate gene association studies and genome-wide linkage studies in humans, as well as quantitative trait locus mapping animal models are reviewed separately. Studies of transgenic and knockout mice models relevant to osteoporosis are summarized. An important extension of this update is incorporation of functional genomic studies (including DNA microarrays and proteomics) on osteogenesis and osteoporosis, in light of the rapid advances and the promising prospects of the field. Comments are made on the most notable findings and representative studies for their potential influence and implications on our present understanding of genetics of osteoporosis. The format adopted by this review should be ideal for accommodating future new advances and studies.

Animals↗
PubMed2005

Individualised cancer therapeutics: dream or reality? Therapeutics construction.

The analysis of DNA microarray and proteomic data, and the subsequent integration into functional expression sets, provides a circuit map of the hierarchical cellular networks responsible for sustaining the viability and environmental competitiveness of cancer cells, that is, their robust systematics. These technologies can be used to 'snapshot' the unique patterns of molecular derangements and modified interactions in cancer, and allow for strategic selection of therapeutics that best match the individual profile of the tumour. This review highlights technology that can be used to selectively disrupt critical molecular targets and describes possible vehicles to deliver the synthesised molecular therapeutics to the relevant cellular compartments of the malignant cells. RNA interference (RNAi) involves a group of evolutionarily conserved gene silencing mechanisms in which small sequences of double-stranded RNA or intrinsic antisense RNA trigger mRNA cleavage or translational repression, respectively. Although RNAi molecules can be synthesised to 'silence' virtually any gene, even if upregulated, a mechanism for selective delivery of RNAi effectors to sites of malignant disease remains challenging. The authors will discuss gene-modified conditionally replicating viruses as candidate vehicles for the delivery of RNAi.

Animals↗
PubMed2003

Engineered catalytic RNA and DNA : new biochemical tools for drug discovery and design.

Since the fundamental discovery that RNA catalyzes critical biological reactions, the conceptual and practical utility of nucleic acid catalysts as molecular therapeutic and diagnostic agents continually develops. RNA and DNA catalysts are particularly attractive tools for drug discovery and design due to their relative ease of synthesis and tractable rational design features. Such catalysts can intervene in cellular or viral gene expression by effectively destroying virtually any target RNA, repairing messenger RNAs derived from mutant genes, or directly disrupting target genes. Consequently, catalytic nucleic acids are apt tools for dissecting gene function and for effecting gene pharmacogenomic strategies. It is in this capacity that RNA and DNA catalysts have been most widely utilized to affect gene expression of medically relevant targets associated with various disease states, where a number of such catalysts are presently being evaluated in clinical trials. Additionally, biotechnological prospects for catalytic nucleic acids are seemingly unlimited. Controllable nucleic acid catalysts, termed allosteric ribozymes or deoxyribozymes, form the basis of effector or ligand-dependent molecular switches and sensors. Allosteric nucleic acid catalysts promise to be useful tools for detecting and scrutinizing the function of specified components of the metabolome, proteome, transcriptome, and genome. The remarkable versatility of nucleic acid catalysis is thus the fountainhead for wide-ranging applications of ribozymes and deoxyribozymes in biomedical and biotechnological research.

Animals↗
PubMed2002

Tuberculosis drug targets.

Despite the availability of the BCG vaccine and chemotherapy, tuberculosis (TB) remains a leading infectious killer worldwide. The recent rise of TB and especially the alarming increase of drug-resistant TB call for urgent need to develop new anti-TB drugs. Lengthy chemotherapy and increasing emergence of drug-resistant strains pose a significant problem for effective control. The need for a lengthy TB therapy is a consequence of the presence of persistent Mycobacterium tuberculosis, not effectively killed by current anti-TB agents. A list of new drug candidates along with proposed targets for intervention is described. Recent advances in the knowledge of the biology of the organism and the availability of the genome sequence provide a wide range of novel targets for drug design. Gene products involved in controlling vital aspects of mycobacterial metabolism, persistence, virulence and cell wall synthesis would be attractive targets. It is expected that the application of functional genomics tools, such as microarray and proteomics, in combination with modern approaches, such as structure-based drug design and combinatorial chemistry to biology-based targets, will lead to the development of new drugs that are not only active against drug-resistant TB but also can shorten the course of TB therapy.

Animals↗
PubMed2004

Cellular and physiological effects of short-chain fatty acids.

Short chain fatty acids (SCFA) have multiple in vivo and in vitro effects including cell cycle arrest and induction of protein synthesis, differentiation, and apoptosis. Butyrate or derivatives have promise for treating inflammatory bowel disease and colon cancer. Genomic and proteomic analysis have generated new knowledge on function and applications for SCFA.

Animals↗
PubMed2001

Biochip technologies in cancer research.

Development of high-throughput 'biochip' technologies has dramatically enhanced our ability to study biology and explore the molecular basis of disease. Biochips enable massively parallel molecular analyses to be carried out in a miniaturized format with a very high throughput. This review will highlight applications of the various biochip technologies in cancer research, including analysis of 1) disease predisposition by using single-nucleotide polymorphism (SNP) microarrays, 2) global gene expression patterns by cDNA microarrays, 3) concentrations, functional activities or interactions of proteins with proteomic biochips, and 4) cell types or tissues as well as clinical endpoints associated with molecular targets by using tissue microarrays. One can predict that individual cancer risks can, in the future, be estimated accurately by a microarray profile of multiple SNPs in critical genes. Diagnostics of cancer will be facilitated by biochip readout of activity levels of thousands of genes and proteins. Biochip diagnostics coupled with informatics solutions will form the basis of individualized treatment decisions for cancer patients.

Computational Biology↗
PubMed2007

Hepatitis B virus-induced oncogenesis.

Hepatocellular carcinoma (HCC) is one of the most common cancers in the world with an annual incidence of more than 500000 in the year 2000. Its incidence is rising in many countries. Recently, it has been estimated that about 53% of HCC cases in the world are related to hepatitis B virus (HBV). The epidemiological association of HBV with HCC is well established. In recent studies, it was revealed that HBsAg carriers have a 25-37 times increased risk of developing HCC as compared to non-infected people. At present, HBV-associated carcinogenesis can be seen as a multi-factorial process that includes both direct and indirect mechanisms that might act synergistically. The integration of HBV DNA into the host genome occurs at early steps of clonal tumor expansion. The integration has been shown in a number of cases to affect a variety of cancer-related genes and to exert insertional mutagenesis. The permanent liver inflammation, induced by the immune response, resulting in a degeneration and regeneration process confers to the accumulation of critical mutations in the host genome. In addition to this, the regulatory proteins HBx and the PreS2 activators that can be encoded by the integrate exert a tumor promoter-like function resulting in positive selection of cells producing a functional regulatory protein. Gene expression profiling and proteomic techniques may help to characterize the molecular mechanisms driving HBV-associated carcinogenesis, and thus potentially identify new strategies in diagnosis and therapy.

Carcinoma, Hepatocellular↗
PubMed2003

New drug targets for Mycobacterium tuberculosis.

In spite of the availability of effective chemotherapy and Bacille-Calmette-Guerin (BCG) vaccine, tuberculosis remains a leading infectious killer world-wide. Many factors such as, human immunodeficiency virus (HIV) co-infection, drug resistance, lack of patient compliance with chemotherapy, delay in diagnosis, variable efficacy of BCG vaccine and various other factors contribute to the mortality due to tuberculosis. In spite of the new advances in understanding the biology of Mycobacterium tuberculosis, and availability of functional genomic tools, such as microarray and proteomics, in combination with modern approaches, no new drug has been developed in the past 30 yr. Therefore, there is an urgent need to identify new drug targets in mycobacteria and eventually, develop new drugs. The release of the complete genome sequence of M. tuberculosis has facilitated a more rational, and directional approach to search for new drug targets. In general, gene products involved in mycobacterial metabolism, persistence, transcription, cell wall synthesis and virulence would be possible targets for the development of new drugs. The exploitation of host cell signaling pathways for the benefit of the pathogen is a phenomenon that deserves to be looked into with a new perspective in the current scenario to combat M. tuberculosis. Reversible phosphorylation and dephosphorylation, which are carried out by specific protein kinases and phosphatases have been shown to modify the host proteins and help in the establishment of disease by several pathogenic bacteria. In this review, we discuss some possible drug targets for M. tuberculosis.

Animals↗
PubMed2005

Down-regulation of RAB6KIFL/KIF20A, a kinesin involved with membrane trafficking of discs large homologue 5, can attenuate growth of pancreatic cancer cell.

To identify novel molecular targets for treatment of pancreatic ductal adenocarcinoma (PDAC), we generated precise gene expression profiles of PDACs on a genome-wide cDNA microarray after populations of tumor cells were purified by laser microdissection. Through functional analysis of genes that were transactivated in PDACs, we identified RAB6KIFL as a candidate for development of drugs to treat PDACs at the molecular level. Knockdown of endogenous RAB6KIFL expression in PDAC cell lines by small interfering RNA drastically attenuated growth of those cells, suggesting an essential role for the gene product in maintaining viability of PDAC cells. RAB6KIFL belongs to the kinesin superfamily of motor proteins, which have critical functions in trafficking of molecules and organelles. Proteomics analyses using a polyclonal anti-RAB6KIFL antibody identified one of the cargoes transported by RAB6KIFL as discs, large homologue 5 (DLG5), a scaffolding protein that may link the vinexin-beta-catenin complex at sites of cell-cell contact. Like RAB6KIFL, DLG5 was overexpressed in PDACs, and knockdown of endogenous DLG5 by small interfering RNA significantly suppressed the growth of PDAC cells as well. Decreased levels of endogenous RAB6KIFL in PDAC cells altered the subcellular localization of DLG5 from cytoplasmic membranes to cytoplasm. Our results imply that collaboration of RAB6KIFL and DLG5 is likely to be involved in pancreatic carcinogenesis. These molecules should be promising targets for development of new therapeutic strategies for PDACs.

Cell Division↗
PubMed2006

Arabidopsis thaliana proteomics: from proteome to genome.

Proteomics has become an important approach for investigating cellular processes and network functions. Significant improvements have been made during the last few years in technologies for high-throughput proteomics, both at the level of data analysis software and mass spectrometry hardware. As proteomics technologies advance and become more widely accessible, efforts of cataloguing and quantifying full proteomes are underway to complement other genomics approaches, such as RNA and metabolite profiling. Of particular interest is the application of proteome data to improve genome annotation and to include information on post-translational protein modifications with the annotation of the corresponding gene. This type of analysis requires a paradigm shift because amino acid sequences must be assigned to peptides without relying on existing protein databases. In this review, advances and current limitations of full proteome analysis are briefly highlighted using the model plant Arabidopsis thaliana as an example. Strategies to identify peptides are also discussed on the basis of MS/MS data in a protein database-independent approach.

Arabidopsis↗
PubMed2001

Functional food ingredients against colorectal cancer. An example project integrating functional genomics, nutrition and health.

Functional Food Ingredients Against Colorectal Cancer is one of the first European Union funded Research Projects at the cross-road of functional genomics [comprising transcriptomics, the measurement of the expression of all messengers RNA (mRNAs) and proteomics, the measurement of expression/state of all proteins], nutrition and human health. The goal of Functional Food Ingredients Against Colorectal Cancer is to develop a colon epithelial cell line-based screening assay for nutrients with presumed anti-colorectal carcinogenic properties. Genes involved in colon carcinogenesis are identified at the RNA and protein level, using a variety of methods (subtractive hybridisation, DNA microarray, proteomics) in combination with models for colorectal cancer development (human biopsies, rat model for colorectal carcinogenesis, colorectal cancer epithelial cell lines). Secondly, colorectal cancer epithelial cell lines are selected, in terms of their capacity to undergo gene/protein expression changes representing different phases in the colorectal carcinogenesis. Thirdly, these cell lines are used to determine the effects of nutrients with presumed anti-carcinogenic properties (e.g. resveratrol, flavonoids) on functional genomics-derived endpoints. Once validated against the effects of these nutrients in in vivo animal models and classical biomarkers for colorectal carcinogenesis, these cell line models combined with functional genomics represent useful tools to study colorectal carcinogenesis and screen for nutrients with anti-carcinogenic properties.

Animals↗
PubMed2003

Peptide libraries: at the crossroads of proteomics and bioinformatics.

Peptide libraries offer a valuable means for providing functional information regarding protein-modifying enzymes and protein interaction domains. Library approaches have become increasingly useful as high-throughput strategies for the analysis of large numbers of new proteins identified as a result of genome-sequencing efforts. Recent developments in the field have produced faster methods with broadened applicability. Crucially, new computational and biochemical tools have emerged that facilitate identification of interaction partners and substrates for proteins on the basis of their peptide selectivity profiles. Such combinations of proteomics-scale experimental approaches with bioinformatics tools hold great promise for the elucidation of protein interaction networks and signal transduction pathways in living cells.

Computational Biology↗
PubMed2002

Screening and selection methods for large-scale analysis of protein function.

High-throughput assays hold tremendous promise for protein engineering and proteomics. With powerful assays it should be possible to evolve, for example, a stereoselective esterase for the chemical synthesis or a site-specific endonuclease for biomedical research. Entire cDNA libraries, which encode all of the proteins expressed in a given organism or cell line, should simply be passed through a battery of biochemical assays to determine the function of each individual protein. Herein we look at the types of assays that have been developed and how close we are to our goals of engineering proteins with new activities as well as rapidly assigning function to the thousands of proteins that make up each genome.

Amino Acid Sequence↗
PubMed2026

H-NOX and NosP Regulate Flagellar Protein and Virulence Factor Production in Vibrio cholerae.

The ability of Vibrio cholerae to transition between motile and sessile forms in the environment and in the host is critical to its survival and virulence. The molecular cues, sensor proteins, and signaling pathways mediating these transitions are highly complex and often overlapping. Nevertheless, a detailed understanding of them is critical for understanding the persistence and pathogenesis of this deadly pathogen. Nitric oxide (NO) functions as an important signaling molecule in many bacteria, affecting biofilm formation, motility, and virulence, often through interaction with heme protein sensors. The genome of V. cholerae encodes two such sensors called H-NOX and NosP. Here we constructed a Δhnox/nosP mutant and employed a multi-omics methodology that combines tandem-mass-tag (TMT)-based quantitative proteomics, phosphoproteomics, and targeted metabolomics to investigate the function of these sensors. A set of 258 proteins was differentially expressed in the mutant that included many proteins involved in flagellar biosynthesis and motility as well as critical virulence factors, iron acquisition systems, and metabolic enzymes. Many of the identified genes are also part of the ferric uptake regulator (Fur) regulon and iron-dependent transcriptional repression of several Fur targets was disrupted. Phosphoproteomics analysis also revealed proteins involved in motility and virulence as differentially phosphorylated in the mutant strain. In most cases, these phosphoproteins have not been previously observed and provide a wealth of new targets for investigating mechanisms of V. cholerae signaling. Taken together, this work illustrates a role for H-NOX and NosP in promoting factors important for infection while suppressing those important for environmental survival, suggesting a function in priming the organism for infection and/or maintaining the infectious phenotype.

Journal Article↗
PubMed2004

Circulating nucleic acids and proteomics of plasma/serum: clinical utility.

Circulating tumor-specific nucleic acids have been identified in plasma, serum, and other body fluids from cancer patients with tumors originating in almost any organ site. Polymerase chain reaction provides a highly sensitive and specific technique for the detection of these genetic changes in a limited amount of tissue/fluid. The presence of elevated levels of free DNA/RNA in many medical conditions, malignancy, and infectious processes is being investigated for screening, diagnosis, prognosis, surveillance for occult disease progression, identifying potential therapeutic targets, and monitoring treatment response. Additionally, elevated fetal DNA/RNA in maternal blood is being used to determine gender identity, assess chromosomal abnormalities, and monitor pregnancy-associated complications. Questions remain on the etiology, characteristics, stability, and potential pathologic consequences of cell-free DNA/RNA in the circulation. Nevertheless, nucleic acid-based assays that monitor plasma, serum, and body fluids provide a noninvasive, facile, and practical method for assessing patients. Proteomic profiling may prove complementary to a total functionality approach in providing a comprehensive evaluation of the patient's disease.

Biomarkers, Tumor↗
PubMed2002

Proteomic profiling of mechanistically distinct enzyme classes using a common chemotype.

Proteomics research requires methods to characterize the expression and function of proteins in complex mixtures. Toward this end, chemical probes that incorporate known affinity labeling agents have facilitated the activity-based profiling of certain enzyme families. To accelerate the discovery of proteomics probes for enzyme classes lacking cognate affinity labels, we describe here a combinatorial strategy. Members of a probe library bearing a sulfonate ester chemotype were screened against complex proteomes for activity-dependent protein reactivity, resulting in the labeling of at least six mechanistically distinct enzyme classes. Surprisingly, none of these enzymes represented targets of previously described proteomics probes. The sulfonate library was used to identify an omega-class glutathione S-transferase whose activity was upregulated in invasive human breast cancer lines. These results indicate that activity-based probes compatible with whole-proteome analysis can be developed for numerous enzyme classes and applied to identify enzymes associated with discrete pathological states.

Affinity Labels↗
PubMed2005

Proteomics in nutrition research: principles, technologies and applications.

The global profiling of the whole protein complement of the genome expressed in a particular cell or organ, or in plasma or serum, makes it possible to identify biomarkers that respond to alterations in diet or to treatment, and that may have predictive value for the modelling of biological processes. Proteomics has not yet been applied on a large scale in nutritional studies, yet it has advantages over transcriptome profiling techniques in that it directly assesses the entities that carry out the biological functions. The present review summarizes the different approaches in proteomics research, with special emphasis on the current technical 'workhorses': two-dimensional (2D)-PAGE with immobilized pH gradients and protein identification by MS. Using a work-flow approach, we provide information and advice on sample handling and preparation, protein solubilization and pre-fractionation, protein separation by 2D-PAGE, detection and quantification via computer-assisted analysis of gels, and protein identification and characterization techniques by means of MS. Examples from nutritional studies employing proteomics are provided to demonstrate not only the advantages but also the limitations of current proteome analysis platforms.

Electrophoresis, Gel, Two-Dimensional↗