研究者詳細 - 冨田　勝

論文 - 冨田　勝

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Sustained MAPK activation is dependent on continual NGF receptor regeneration

Qiu D., Mao L., Kikuchi S., Tomita M.

Development Growth and Differentiation 46 （ 5 ） 393 - 403 2004年06月

研究論文（研究会，シンポジウム資料等）, 共著, 査読有り, ISSN 00121592

It still remains intriguing how signal specificity is achieved when different signals are relayed by the common intracellular signal transduction pathways. A well documented example for signal specificity determination is found in rat phaeochromocytoma PC12 cells where epidermal growth factor (EGF) stimulation produces a transient mitogen-activated protein kinase (MAPK) activation and leads to cell proliferation while nerve growth factor (NGF) initiates a sustained MAPK activation and induces cell differentiation. In this simulation, we demonstrated that NGF-induced sustained MARK activation may mainly depend on continual regeneration of NGF receptors and that the presence of a small pool of surface receptors is enough to maintain a sustained MAPK activation. On the other hand, MAPK activation is not significantly sensitive to the half-life of internalized receptors and the levels of NGF-specific MAPK phosphatase MAP kinase phosphatase-3 (MKP-3), though cytoplasmic persistence of internalized NGF-bound receptors and the MKP-3 dependent feedback control also contribute to the sustaining of MAPK activation. These results are consistent with the recent experimental evidence that persistent tyrosine receptor kinase A (TrkA) activity is necessary to maintain transcription in the differentiating PC12 cells (Chang et al. 2003) and a sustained Src kinase activity is detected in response to NGF stimulation (Gatti 2003). It is suggested that sustained or transient MAPK activation induced by different growth factor and neurotrophins, which is crucial to their signaling specificity, could be satisfactorily accounted for by their specific receptor turnover kinetics rather than by the activation of specific downstream signaling cascades.

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Characterization of the splice sites in GT-AG and GC-AG introns in higher eukaryotes using full-length cDNAs

Kitamura-Abe S., Itoh H., Washio T., Tsutsumi A., Tomita M.

Journal of Bioinformatics and Computational Biology 2 （ 2 ） 309 - 331 2004年06月

ISSN 02197200

For the purpose of analyzing the relation between the splice sites and the order of introns, we conducted the following analysis for the GT-AG and GC-AG splice site groups. First, the pre-mRNAs of H. sapiens, M. musculus, D. melanogaster, A. thaliana and O. sativa were sampled by mapping the full-length cDNA to the genomes. Next, the consensus sequences at different regions of pre-mRNAs were analyzed in the five species. We also investigated the mononucleotide and dinucleotide frequencies in the extensive regions around the 5′ splice sites (5′ss) and 3′ splice sites (3′ss). As a result, differential frequencies of nucleotides at the first 5′ss in both the GT-AG and GC-AG splice site groups were observed in A. thaliana and O. sativa pre-mRNAs. The trend, which indicates that GC 5′ss possess strong consensus sequences, was observed not only in mammalian pre-mRNAs but also in the pre-mRNAs of D. melanogaster, A. thaliana and O. sativa. Furthermore, we examined the consensus sequences of the constitutive and alternative splice sites. It was suggested that in the case of the alternative GC-AG introns, the tendency to have a weak consensus sequence at 5′ss is different between H. sapiens and M. musculus pre-mRNAs. © Imperial College Press.

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Application of capillary electrophoresis-mass spectrometry to syntheitc in vitro glycolysis studies

Itoh A., Ohashi Y., Soga T., Mori H., Nishioka T. and Tomita M.

Electrophoresis 25 1996-2002 2004年

研究論文（学術雑誌）, 共著

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Simultaneous determination of the main metabolites in rice leaves using capillary electrophoresis mass spectrometry and capillary electrophoresis diode array detection

Sato, S., Soga, T., Nishioka, T. and Tomita, M.

Plant Journal 40 （ 1 ） 151-163 2004年

研究論文（学術雑誌）, 共著, 査読有り

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A general computational model of mitochondrial metabolism in a whole organelle scale

Yugi K., Tomita M.

Bioinformatics 20 （ 20 ） 1795-1796 - 1796 2004年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 13674803

Summary: A computational tool for mitochondrial systems biology has been developed as a simulation model of E-Cell2, a publicly available simulation system. The general model consists of 58 enzymatic reactions and 117 metabolites, representing the respiratory chain, the TCA cycle, the fatty acid β-oxidation and the inner-membrane transport system. It is based on previously published enzyme kinetics studies in the literature; we have successfully integrated and packaged them into a single large model. The model can be easily extended and modified so that mitochondrial biologists/physiologists can integrate their own models and evaluate them in the context of the whole organelle metabolism. © Oxford University Press 2004; all rights reserved.

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Position-specific expression of Hox genes along the gastrointestinal tract.

Yahagi N., Kosaki R., Ito T., Mitsuhashi T., Shimada H., Tomita M., Takahashi T., Kosaki K.

Congenital anomalies 44 （ 1 ） 18-26 - 26 2004年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 09143505

Hox genes play a critical role in morphogenesis of the early embryo along the anteroposterior axis. In mammals, 39 Hox genes with extensive homology are organized into 13 paralogous groups, forming four clusters on four separate chromosomes. The genes within each cluster are arranged in a 3' to 5' direction and expressed in a temporally and spatially coordinated manner along the anteroposterior axis in the vertebrae, limbs and viscera, including the gastrointestinal tract, but little is known about their spatial expression in the adult gastrointestinal tract. We used the quantitative polymerase chain reaction (PCR) intercalater method with SYBR Green to quantify human Hox gene expression in the adult gastrointestinal tract tissue: esophagus, stomach, duodenum, jejunum, ileum, ileocecum, cecum, ascending colon, transverse colon, descending colon and rectum. Hox gene expression was normalized to glyceraldehyde-3-phosphate-dehydrogenase (GAPDH) gene expression. The spatial expression pattern was analyzed by the multivariate method. The expression level of all 39 Hox genes could be measured in a reproducible manner. Genes with higher expression in the foregut-derived segments tended to have lower expression in hindgut-derived segments, whereas those with low expression in the former tended to have higher in the latter. Principal components analysis and permax analysis revealed a position-specific expression pattern of Hox genes along the anteroposterior axis of the adult gastrointestinal tract. The pattern recapitulates the expression pattern in the embryonic gastrointestinal tract. We suggest that Hox genes may play a pivotal role in the position-specific regenerative process of intestinal epithelial cells.

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A multi-algorithm, multi-timescale method for cell simulation

Takahashi K., Kaizu K., Hu B., Tomita M.

Bioinformatics 20 （ 4 ） 538-546 - 546 2004年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 13674803

Motivation: Many important problems in cell biology require the dense nonlinear interactions between functional modules to be considered. The importance of computer simulation in understanding cellular processes is now widely accepted, and a variety of simulation algorithms useful for studying certain subsystems have been designed. Many of these are already widely used, and a large number of models constructed on these existing formalisms are available. A significant computational challenge is how we can integrate such sub-cellular models running on different types of algorithms to construct higher order models. Results: A modular, object-oriented simulation meta-algorithm based on a discrete-event scheduler and Hermite polynomial interpolation has been developed and implemented. It is shown that this new method can efficiently handle many components driven by different algorithms and different timescales. The utility of this simulation framework is demonstrated further with a 'composite' heat-shock response model that combines the Gillespie - Gibson stochastic algorithm and deterministic-differential equations. Dramatic improvements in performance were obtained without significant accuracy drawbacks. A multi-timescale demonstration of coupled harmonic oscillators is also shown. © Oxford University Press 2004; all rights reserved.

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Identification of the first archaeal Type 1 RNase H gene from Halobacterium sp. NRC-1: Archaeal RNase HI can cleave an RNA-DNA junction

Ohtani N., Yanagawa H., Tomita M., Itaya M.

Biochemical Journal 381 （ 3 ） 795-802 - 802 2004年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 02646021

All the archaeal genomes sequenced to date contain a single Type 2 RNase H gene. We found that the genome of a halophilic archaeon, Halobacterium sp. NRC-1, contains an open reading frame with similarity to Type 1 RNase H. The protein encoded by the Vng0255c gene, possessed amino acid sequence identities of 33 % with Escherichia coli RNase HI and 34 % with a Bacillus subtilis RNase HI homologue. The B. subtilis RNase HI homologue, however, lacks amino acid sequences corresponding to a basic protrusion region of the E. coli RNase HI, and the Vng0255c has the similar deletion. As this deletion apparently conferred a complete loss of RNase H activity on the B. subtilis RNase HI homologue protein, the Vng0255c product was expected to exhibit no RNase H activity. However, the purified recombinant Vng0255c protein specifically cleaved an RNA strand of the RNA/DNA hybrid in vitro, and when the Vng0255c gene was expressed in an E. coli strain MIC2067 it could suppress the temperature-sensitive growth defect associated with the loss of RNase H enzymes of this strain. These results in vitro and in vivo strongly indicate that the Halobacterium Vng0255c is the first archaeal Type 1 RNase H. This enzyme, unlike other Type 1 RNases H, was able to cleave an Okazaki fragment-like substrate at the junction between the 3′-side of ribonucleotide and 5′-side of deoxyribonucleotide. It is likely that the archaeal Type 1 RNase H plays a role in the removal of the last ribonucleotide of the RNA primer from the Okazaki fragment during DNA replication.

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Toward large-scale modeling of the microbial cell for computer simulation

Ishii N., Robert M., Nakayama Y., Kanai A., Tomita M.

Journal of Biotechnology 113 （ 1-3 ） 281-294 - 294 2004年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 01681656

In the post-genomic era, the large-scale, systematic, and functional analysis of all cellular components using transcriptomics, proteomics, and metabolomics, together with bioinformatics for the analysis of the massive amount of data generated by these "omics" methods are the focus of intensive research activities. As a consequence of these developments, systems biology, whose goal is to comprehend the organism as a complex system arising from interactions between its multiple elements, becomes a more tangible objective. Mathematical modeling of microorganisms and subsequent computer simulations are effective tools for systems biology, which will lead to a better understanding of the microbial cell and will have immense ramifications for biological, medical, environmental sciences, and the pharmaceutical industry.In this review, we describe various types of mathematical models (structured, unstructured, static, dynamic, etc.), of microorganisms that have been in use for a while, and others that are emerging. Several biochemical/cellular simulation platforms to manipulate such models are summarized and the E-Cell system 1 developed in our laboratory is introduced. Finally, our strategy for building a "whole cell metabolism model", including the experimental approach, is presented. © 2004 Elsevier B.V. All rights reserved.

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The 'weighted sum of relative entropy': A new index for synonymous codon usage bias

Suzuki H., Saito R., Tomita M.

Gene 335 （ 335 ） 19-23 - 23 2004年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 03781119

Shannon entropy from information theory has been applied to estimate the degree of deviation from equal usage of synonymous codons; however, previous attempts have failed to take into account all three aspects of amino acid usage, i.e. (i) the number of distinct amino acids, (ii) their relative frequencies, and (iii) their degree of codon degeneracy. A new index taking into account all of these aspects is proposed. The index, designated as the 'weighted sum of relative entropy' (Ew), is defined as the sum of the relative entropy of each amino acid weighted by its relative frequency in the sequence. In this paper, we demonstrate that Ew allows us to avoid some amino acid usage biases and can yield results contradictory to those obtained by previous methods. © 2004 Elsevier B.V. All rights reserved.

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Qualitative and quantitative analysis of amino acids by capillary electrophresis Electrospray ionization tandem mass spectrometry

Soga, T., Kakazu Yuji, Robert, M., Tomita, M. and Nishioka, T

Electrophoresis （ 25 ） 1964-1972 2004年

研究論文（学術雑誌）, 共著, 査読有り

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On dynamics of overlapping genes in bacterial genomes

Fukuda Y., Nakayama Y., Tomita M.

Gene 323 （ 1-2 ） 181 - 187 2003年12月

ISSN 03781119

A genome-wide computational analysis of overlapping genes in various prokaryotic genomes was conducted to study the evolutionary rates of the formation and degradation of overlapping genes. Overlapping genes are adjacent genes that overlap partially or entirely. Overlapping gene pairs extracted from complete bacterial genome sequences were classified into three directional patterns, namely, 'convergent' (→←), 'unidirectional' (→→), and 'divergent' (←→). Divergent overlapping genes were rare compared to the other two patterns. We also compared the structures of overlapping genes that are not conserved in the homologous genes of different species. We found that overlapping genes are mainly generated from gene pairs with short intergenic regions. Overlapping genes caused by mutations at the 3′-end of genes occur more frequently than overlapping genes generated by mutations at the 5′-end of genes in closely related species. In contrast, gene overlaps due to mutations at the 5′-ends accumulate in distant species. These differences presumably correlate to the genomic divergence among species. The evolution of these overlapping gene structures is probably related to the evolutionary time scale, which suggests that the evolution of overlapping genes occurs at a universal mutation rate across species. © 2003 Elsevier B.V. All rights reserved.

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A novel feature of microsatellites in plants: A distribution gradient along the direction of transcription

Fujimori S., Washio T., Higo K., Ohtomo Y., Murakami K., Matsubara K., Kawai J., Carninci P., Hayashizaki Y., Kikuchi S., Tomita M.

FEBS Letters 554 （ 1-2 ） 17 - 22 2003年11月

研究論文（学術雑誌）, 単著, ISSN 0014-5793

A computer-based analysis was conducted to assess the characteristics of microsatellites in transcribed regions of rice and Arabidopsis. In addition, two mammals were simultaneously analyzed for a comparative analysis. Our analyses confirmed a novel plant-specific feature in which there is a gradient in microsatellite density along the direction of transcription. It was also confirmed that pyrimidine-rich microsatellites are found intensively near the transcription start sites, specifically in the two plants, but not in the mammals. Our results suggest that microsatellites located at high frequency in the 5′-flanking regions of plant genes can potentially act as factors in regulating gene expression. © 2003 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

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Kinetic simulation of signal transduction system in hippocampal long-term potentiation with dynamic modeling of protein phosphatase 2A

Kikuchi S., Fujimoto K., Kitagawa N., Fuchikawa T., Abe M., Oka K., Takei K., Tomita M.

Neural Networks 16 （ 9 ） 1389 - 1398 2003年11月

ISSN 08936080

We modeled and analyzed a signal transduction system of long-term potentiation (LTP) in hippocampal post-synapse. Bhalla and Iyengar [Science 283(1999) 381] have developed a hippocampal LTP model. In the conventional model, the concentration of protein phosphatase 2A (PP2A) was fixed. However, it was reported that dynamic inactivation of PP2A was essential for LTP [J. Neurochem. 74 (2000) 807]. We introduced a dynamic modeling of PP2A; inactivation (phosphorylation) of PP2A by calcium/calmodulin-dependent protein kinase II (CaMKII) in the presence of calcium/calmodulin, self-activation (autodephosphorylation) of PP2A, and inactivation (dephosphorylation) of CaMKII by PP2A. This model includes complex feedback loops; both CaMKII and PP2A are autoactivated, while they inactivate each other. Moreover, we proposed an analysis strategy for model validation by applying the results of sensitivity analysis. In our system, calcineurin (CaN) played an essential role, rather than the activation of protein kinase C (PKC) as documented in the conventional model. From results of the analysis of our model, we found the following robustness as characteristics of bistability in our model: (1) PP2A reactions against calcium ion (Ca2+) perturbation; (2) PP2A inactivation against PP2A increase; (3) protein phosphatase 1 (PP1) activation against PF2A increase; and (4) PP2A reactions against PP2A initial concentration. These properties facilitated LTP induction in our system. We showed that another mechanism could introduce bistable behavior by adding dynamic reactions of PP2A. © 2003 Elsevier Ltd. All rights reserved.

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E-Cell 2: Multi-platform E-Cell simulation system

Takahashi K., Ishikawa N., Sadamoto Y., Sasamoto H., Ohta S., Shiozawa A., Miyoshi F., Naito Y., Nakayama Y., Tomita M.

Bioinformatics 19 （ 13 ） 1727 - 1729 2003年09月

研究論文（学術雑誌）, 単著, ISSN 1367-4803

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Comparative study of translation termination sites and release factors (RF1 and RF2) in procaryotes

Ozawa Y., Saito R., Washio T., Tomita M.

Journal of Molecular Evolution 56 （ 6 ） 665 - 672 2003年06月

ISSN 00222844

Translation termination is catalyzed by release factors that recognize stop codons. However, previous works have shown that in some bacteria, the termination process also involves bases around stop codons. Recently, Ito et al, analyzed release factors and identified the amino acids therein that recognize stop codons. However, the amino acids that recognize bases around stop codons remain unclear. To identify the candidate amino acids that recognize the bases around stop codons, we aligned the protein sequences of the release factors of various bacteria and searched for amino acids that were conserved specifically in the sequence of bacteria that seemed to regulate translation termination by bases around stop codons. As a result, species having several highly conserved residues in RF1 and RF2 showed positive correlations between their codon usage bias and conservation of the bases around the stop codons. In addition, some of the residues were located very close to the SPF motif, which deciphers stop codons. These results suggest that these conserved amino acids enable the release factors to recognize the bases around the stop codons.

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Dynamics modeling of genetic networks using genetic algorithm and S-system

Kikuchi S., Tominaga D., Arita M., Takahashi K., Tomita M.

Bioinformatics 19 （ 5 ） 643 - 650 2003年03月

ISSN 13674803

Motivation: The modeling of system dynamics of genetic networks, metabolic networks or signal transduction cascades from time-course data is formulated as a reverse-problem. Previous studies focused on the estimation of only network structures, and they were ineffective in inferring a network structure with feedback loops. We previously proposed a method to predict not only the network structure but also its dynamics using a Genetic Algorithm (GA) and an S-system formalism. However, it could predict only a small number of parameters and could rarely obtain essential structures. In this work, we propose a unified extension of the basic method. Notable improvements are as follows: (1) an additional term in its evaluation function that aims at eliminating futile parameters; (2) a crossover method called Simplex Crossover (SPX) to improve its optimization ability; and (3) a gradual optimization strategy to increase the number of predictable parameters. Results: The proposed method is implemented as a C program called PEACE1 (Predictor by Evolutionary Algorithms and Canonical Equations 1). Its performance was compared with the basic method. The comparison showed that: (1) the convergence rate increased about 5-fold; (2) the optimization speed was raised about 1.5-fold; and (3) the number of predictable parameters was increased about 5-fold. Moreover, we successfully inferred the dynamics of a small genetic network constructed with 60 parameters for 5 network variables and feedback loops using only time-course data of gene expression.

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E-Cell simulation system and its application to the modeling of circadian rhythm

Miyoshi F., Nakayama Y., Tomita M.

Seikagaku 75 （ 1 ） 5-16 - 16 2003年01月

研究論文（学術雑誌）, 単著, ISSN 0037-1017

G-language genome analysis environment: A workbench for nucleotide sequence data mining

Arakawa, K., Mori, K., Ikeda, K., Matsuzaki, T., Kobayashi, Y., and Tomita, M.

Bioinformatics 19 （ 2 ） 305 - 306 2003年

研究論文（学術雑誌）, 共著, ISSN 13674803

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The systems biology markup language (SBML): A medium for representation and exchange of biochemical network models

Hucka M., Finney A., Sauro H.M., Bolouri H., Doyle J.C., Kitano H., Arkin A.P., Bornstein B.J., Bray D., Cornish-Bowden A., Cuellar A.A., Dronov S., Gilles E.D., Ginkel M., Gor V., Goryanin I.I., Hedley W.J., Hodgman T.C., Hofmeyr J.H., Hunter P.J., Juty N.S., Kasberger J.L., Kremling A., Kummer U., Le Novère N., Loew L.M., Lucio D., Mendes P., Minch E., Mjolsness E.D., Nakayama Y., Nelson M.R., Nielsen P.F., Sakurada T., Schaff J.C., Shapiro B.E., Shimizu T.S., Spence H.D., Stelling J., Takahashi K., Tomita M., Wagner J., Wang J.

Bioinformatics 19 （ 4 ） 524 - 531 2003年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 13674803

Motivation: Molecular biotechnology now makes it possible to build elaborate systems models, but the systems biology community needs information standards if models are to be shared, evaluated and developed cooperatively. Results: We summarize the Systems Biology Markup Language (SBML) Level 1, a free, open, XML-based format for representing biochemical reaction networks. SBML is a software-independent language for describing models common to research in many areas of computational biology, including cell signaling pathways, metabolic pathways, gene regulation, and others.

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冨田 勝

論文 - 冨田 勝

冨田　勝

論文 - 冨田　勝