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Biomedical subjects

Toru Nishikawa

Publications and source records attributed to Toru Nishikawa.

At least 19 recordsLinked to original sources
PubMed2006

p18Ink4c, but not p27Kip1, collaborates with Men1 to suppress neuroendocrine organ tumors.

Mutant mice lacking both cyclin-dependent kinase (CDK) inhibitors p18(Ink4c) and p27(Kip1) develop a tumor spectrum reminiscent of human multiple endocrine neoplasia (MEN) syndromes. To determine how p18 and p27 genetically interact with Men1, the tumor suppressor gene mutated in familial MEN1, we characterized p18-Men1 and p27-Men1 double mutant mice. Compared with their corresponding single mutant littermates, the p18(-/-); Men1(+/-) mice develop tumors at an accelerated rate and with an increased incidence in the pituitary, thyroid, parathyroid, and pancreas. In the pituitary and pancreatic islets, phosphorylation of the retinoblastoma (Rb) protein at both CDK2 and CDK4/6 sites was increased in p18(-/-) and Men1(+/-) cells and was further increased in p18(-/-); Men1(+/-) cells. The remaining wild-type Men1 allele was lost in most tumors from Men1(+/-) mice but was retained in most tumors from p18(-/-); Men1(+/-) mice. Combined mutations of p27(-/-) and Men1(+/-), in contrast, did not exhibit noticeable synergistic stimulation of Rb kinase activity, cell proliferation, and tumor growth. These results demonstrate that functional collaboration exists between p18 and Men1 and suggest that Men1 may regulate additional factor(s) that interact with p18 and p27 differently.

Alleles↗
PubMed2006

siVirus: web-based antiviral siRNA design software for highly divergent viral sequences.

siVirus (http://siVirus.RNAi.jp/) is a web-based online software system that provides efficient short interfering RNA (siRNA) design for antiviral RNA interference (RNAi). siVirus searches for functional, off-target minimized siRNAs targeting highly conserved regions of divergent viral sequences. These siRNAs are expected to resist viral mutational escape, since their highly conserved targets likely contain structurally/functionally constrained elements. siVirus will be a useful tool for designing optimal siRNAs targeting highly divergent pathogens, including human immunodeficiency virus (HIV), hepatitis C virus (HCV), influenza virus and SARS coronavirus, all of which pose enormous threats to global human health.

Anti-HIV Agents↗
PubMed2006

Effects of repetitive transcranial magnetic stimulation on [11C]raclopride binding and cognitive function in patients with depression.

BACKGROUND: Several studies have demonstrated that repetitive transcranial magnetic stimulation (rTMS) elicits moderate antidepressant effects. Several previous studies suggested that the dopaminergic system might be related to this therapeutic action of rTMS. We attempted to determine the effects of chronic rTMS on central dopaminergic function in depression using positron emission tomography (PET) with [11C]raclopride. METHODS: Nine patients with depression were treated with 10 daily sessions of rTMS (10 Hz, 5 s train, 20 trains at 100% motor threshold per session) over the left dorsolateral prefrontal cortex (DLPFC). Each patient underwent two [11C]raclopride PET scans and neuropsychological tests - before rTMS and 1 day after rTMS. RESULTS: In five patients, the Hamilton Rating Scale for Depression (HRSD) significantly decreased. Patients showed significant improvement in verbal memory following rTMS. There were no changes in [11C]raclopride binding in the caudate nucleus and putamen after rTMS treatment. LIMITATIONS: Our sample size was limited, and our study was an open trial lacking sham-treated controls. CONCLUSION: This study suggests that rTMS may be effective for the treatment of depression and also may improve verbal memory function. We observed no changes in [11C]raclopride binding, suggesting that there was no measurable increase in the release of dopamine at the second PET scan. Several animal studies and healthy human studies have indicated that dopamine can be released soon after acute rTMS. Our results suggest that release of striatal dopamine induced by rTMS may be only transient, or that dopamine release may be attenuated following chronic rTMS.

Adult↗
PubMed2006

Selective serotonin reuptake inhibitors, fluoxetine and paroxetine, attenuate the expression of the established behavioral sensitization induced by methamphetamine.

To obtain an insight into the development of a new pharmacotherapy that prevents the treatment-resistant relapse of psychostimulant-induced psychosis and schizophrenia, we have investigated in the mouse the effects of selective serotonin reuptake inhibitors (SSRI), fluoxetine (FLX) and paroxetine (PRX), on the established sensitization induced by methamphetamine (MAP), a model of the relapse of these psychoses, because the modifications of the brain serotonergic transmission have been reported to antagonize the sensitization phenomenon. In agreement with previous reports, repeated MAP treatment (1.0 mg/kg a day, subcutaneously (s.c.)) for 10 days induced a long-lasting enhancement of the increasing effects of a challenge dose of MAP (0.24 mg/kg, s.c.) on motor activity on day 12 or 29 of withdrawal. The daily injection of FLX (10 mg/kg, s.c.) or PRX (8 mg/kg, s.c.) from 12 to 16 days of withdrawal of repeated MAP administration markedly attenuated the ability of the MAP pretreatment to augment the motor responses to the challenge dose of the stimulant 13 days after the SSRI injection. The repeated treatment with FLX or PRX alone failed to affect the motor stimulation following the challenge of saline and MAP 13 days later. These results suggest that the intermittent and repetitive elevation of serotonergic tone may inhibit the expression of the motor sensitization induced by pretreatment with MAP. It is proposed that clinically available serotonin reuptake inhibitors could be useful for preventing the recurrence of hallucinatory-paranoid state in drug-induced psychosis and schizophrenia.

Animals↗
PubMed2006

Quantitative magnetic resonance spectroscopy of schizophrenia: relationship between decreased N-acetylaspartate and frontal lobe dysfunction.

Numerous studies using proton magnetic resonance spectroscopy (1H-MRS) have detected signal changes in schizophrenia. However, most studies investigated relative concentrations such as N-acetylaspartate/creatine plus phosphocreatine (NAA/Cre) and choline-containing compounds/creatine plus phosphocreatine (Cho/Cre), and individual metabolite concentrations have not been clarified. Using absolute quantification measurement of 1H-MRS, the aim of the present paper was to demonstrate the changes in metabolite concentrations in the frontal lobe of patients with chronic schizophrenia. The 1H-MRS was performed in the left frontal lobe in 14 patients with schizophrenia and in 13 healthy comparison subjects. Individual MRS peak concentration was quantified based on a frequency-domain fitting program: LCModel. The scores on the Positive and Negative Symptoms Scale and Wisconsin Card Sorting Test were used for clinical assessment. The NAA concentration was reduced in schizophrenic patients (average, 7.94 mmol/L, t=2.28, P<0.05) compared with healthy subjects (average=8.45 mmol/L) while choline, creatine or NAA/Cre ratio did not show any differences. The reduction in NAA concentration had a significant correlation with the severity of negative symptoms (r=-0.536, P<0.05) and poor performance in Wisconsin Card Sorting Test (r=-0.544, P<0.05). Using quantitative MRS, decreased NAA concentration was confirmed in the left frontal lobe of schizophrenic patients and was demonstrated to be correlated with negative symptoms and cognitive dysfunction in schizophrenia.

Adult↗
PubMed2005

Inhibition of D-serine accumulation in the Xenopus oocyte by expression of the rat ortholog of human 3'-phosphoadenosine 5'-phosphosulfate transporter gene isolated from the neocortex as D-serine modulator-1.

D-serine in mammalian brains has been suggested to be an endogenous co-agonist of the NMDA-type glutamate receptor. We have explored the molecules regulating D-serine uptake and release from the rat neocortex cDNA library using a Xenopus oocyte expression system, and isolated a cDNA clone designated as dsm-1 (D-serine modulator-1) encoding a protein that reduces the accumulation of D-serine to the oocyte. dsm-1 is the rat orthologue of the human 3'-phosphoadenosine 5'-phosphosulfate transporter 1 (PAPST1) gene. The hydropathy analysis of the deduced amino acid sequence of the Dsm-1 protein predicts the 10 transmembrane domains with a long hydrophobic stretch in the C-terminal like some amino acid transporters. The dsm-1 mRNA is predominantly expressed in the forebrain areas that are enriched with D-serine and NMDA receptors, and in the liver. The transient expression of dsm-1 in COS-7 cells demonstrates a partially Golgi apparatus-related punctuate distribution throughout the cytoplasm with a concentration near the nucleus. dsm-1-expressing oocytes diminishes the sodium-dependent and -independent accumulation of D-serine and the basal levels of the intrinsic D-serine and increases the rate of release of the pre-loaded D-serine. These findings indicate that dsm-1 may, at least in part, be involved in the D-serine translocation across the vesicular or plasma membranes in the brain, and thereby control the extra- and intracellular contents of D-serine.

Amino Acid Sequence↗
PubMed2005

Cloning of a D-serine-regulated transcript dsr-2 from rat cerebral neocortex.

D-serine is now considered to be an endogenous co-agonist of the NMDA receptor in mammalian brain. To obtain insight into the molecular mechanisms underlying D-serine metabolism and function, we explored transcripts that are responsive to D-serine in the neocortex of the 8-day-old infant rat by a differential cloning technique, RNA arbitrarily primed PCR. We isolated a novel D-serine inducible transcript, D-serine-responsive transcript-2 (dsr-2), that was exclusively expressed in the brain. Sequence analysis of the corresponding cDNAs to the transcript revealed that the dsr-2 mRNA consists of 7199 nucleotides with an open reading frame encoding 111 amino acids. The dsr-2 gene was located on the reverse strand within an intron of the neurexin-3alpha gene, mapped to rat chromosome 6q24-31. The regional distribution of the basal expression of dsr-2 and its ontogenic changes in the brain closely correlated with those of free D-serine and of NMDA receptor R2B subunit mRNA, but were somewhat different from those of the neurexin-3alpha transcript. These findings suggest that dsr-2 may be involved in D-serine metabolism and/or function, and in the interactions between D-serine, NMDA receptor and neurexin-3alpha, in mammalian brain.

Adenosine Triphosphatases↗
PubMed2005

The RNA binding protein TLS is translocated to dendritic spines by mGluR5 activation and regulates spine morphology.

Neuronal dendrites, together with dendritic spines, exhibit enormously diverse structure. Selective targeting and local translation of mRNAs in dendritic spines have been implicated in synapse remodeling or synaptic plasticity. The mechanism of mRNA transport to the postsynaptic site is a fundamental question in local dendritic translation. TLS (translocated in liposarcoma), previously identified as a component of hnRNP complexes, unexpectedly showed somatodendritic localization in mature hippocampal pyramidal neurons. In the present study, TLS was translocated to dendrites and was recruited to dendrites not only via microtubules but also via actin filaments. In mature hippocampal pyramidal neurons, TLS accumulated in the spines at excitatory postsynapses upon mGluR5 activation, which was accompanied by an increased RNA content in dendrites. Consistent with the in vitro studies, TLS-null hippocampal pyramidal neurons exhibited abnormal spine morphology and lower spine density. Our results indicate that TLS participates in mRNA sorting to the dendritic spines induced by mGluR5 activation and regulates spine morphology to stabilize the synaptic structure.

Actins↗
PubMed2005

A family-based association study and gene expression analyses of netrin-G1 and -G2 genes in schizophrenia.

BACKGROUND: The netrin-G1 (NTNG1) and -G2 (NTNG2) genes, recently cloned from mouse, play a role in the formation and/or maintenance of glutamatergic neural circuitry. Accumulating evidence strongly suggests that disturbances of neuronal development and the N-methyl-d-aspartate receptor-mediated signaling system might represent a potential pathophysiology in schizophrenia. We therefore set out to examine the genetic contribution of human NTNG1 and NTNG2 to schizophrenia. METHODS: Twenty-one single nucleotide polymorphisms (SNPs) from NTNG1 and 10 SNPs from NTNG2 were analyzed in 124 schizophrenic pedigrees. All genotypes were determined with the TaqMan assay. The expression levels of NTNG1 and NTNG2 were examined in the frontal (Brodmann's Area [BA]11 and BA46) and temporal (BA22) cortices from schizophrenic and control postmortem brains. The isoform-specific expression of NTNG1 splice variants was assessed in these samples. RESULTS: Specific haplotypes encompassing alternatively spliced exons of NTNG1 were associated with schizophrenia, and concordantly, messenger ribonucleic acid isoform expression was significantly different between schizophrenic and control brains. An association between NTNG2 and schizophrenia was also observed with SNPs and haplotypes that clustered in the 5' region of the gene. CONCLUSIONS: The NTNG1 and NTNG2 genes might be relevant to the pathophysiology of schizophrenia.

Adult↗
PubMed2005

Down-regulation of BRCA1-BARD1 ubiquitin ligase by CDK2.

BRCA1, a breast and ovarian tumor suppressor, is a phosphoprotein whose cellular expression level is regulated in a cell cycle-dependent manner. BRCA1 interacts with BARD1 to generate significant ubiquitin ligase activity which catalyzes nontraditional Lys-6-linked polyubiquitin chains. However, it is not clear how the activity is regulated and how this affects BRCA1's multiple cellular functions. Here we show that the ubiquitin ligase activity of BRCA1-BARD1 is down-regulated by CDK2. During the cell cycle, BARD1 expression can largely be categorized into three patterns: moderately expressed in a predominantly unphosphorylated form in early G(1) phase, expressed at low levels in both phosphorylated and unphosphorylated forms during late G(1) and S phases, and highly expressed in its phosphorylated form during mitosis coinciding with BRCA1 expression. CDK2-cyclin A1/E1 and CDK1-cyclin B1 phosphorylate BARD1 on its NH(2) terminus in vivo and in vitro. Intriguingly, the BRCA1-BARD1-mediated in vivo ubiquitination of nucleophosmin/B23 (NPM) and autoubiquitination of BRCA1 are dramatically disrupted by coexpression of CDK2-cyclin A1/E1, but not by CDK1-cyclin B1. The inhibition of ubiquitin ligase activity is not due to the direct effect of the kinases on BARD1 because an unphosphorylatable mutant of BARD1, S148A/S251A/S288A/T299A, is still inhibited by CDK2-cyclin E1. Alternatively, BRCA1 and BARD1 are likely exported to the cytoplasm and their expressions are remarkably reduced by CDK2-cyclin E1 coexpression. Recognizing the importance of cyclin E1 overexpression in breast cancer development, these results suggest a CDK2-BRCA1-NPM pathway that coordinately functions in cell growth and tumor progression pathways.

BRCA1 Protein↗
PubMed2005

Metabolism and functional roles of endogenous D-serine in mammalian brains.

It has now been well established that D-serine, a coagonist for the N-methyl-D-aspartate (NMDA) glutamate receptors (NR1/NR2 type), is maintained at a high concentration in mammalian brains for life and shows a brain-selective and NMDA receptor R2B subunit-related distribution, overturning the hitherto generally accepted theory that D-amino acid is not always present in mammalian tissues. D-Serine in the brain has been shown to be contained in both the glia and neurons and to have specific processes of biosynthesis, extracellular release, uptake, and degradation. Moreover, the selective elimination of D-serine reduces the NMDA receptor-mediated intracellular signaling and long-term potentiation of synaptic connections. Together with the anti-psychotic and anti-ataxic property of D-serine and the pivotal roles of the NMDA receptor in divergent higher brain functions, these observations support the view that the D-amino acid may be involved as an endogenous modulator for the NMDA receptor in various neuropsychiatric functions and their pathological conditions.

Animals↗
PubMed2004

Nucleophosmin/B23 is a candidate substrate for the BRCA1-BARD1 ubiquitin ligase.

The breast and ovarian tumor suppressor BRCA1 forms a heterodimeric RING-type ubiquitin ligase with BARD1 to catalyze untraditional Lys-6-linked polyubiquitin chains. It is not clear how the BRCA1-BARD1 ligase regulates various cellular processes such as DNA repair, cell-cycle progression, transcriptional regulation, and centrosome duplication. Here we report that BRCA1-BARD1 catalyzes the polyubiquitination of nucleolar phosphoprotein nucleophosmin/B23 (NPM). Two different mass spectrometry screens for protein ubiquitinated by BRCA1-BARD1 both identified NPM. NPM interacts with N-terminal fragments of BRCA1 and BARD1 in a manner dependent upon BRCA1-BARD1 heterodimer formation. NPM colocalizes with BRCA1 and BARD1 in mitotic cells suggesting the possibility of NPM regulation by BRCA1-BARD1 during mitosis. BRCA1-BARD1 catalyzes the ubiquitination of NPM in vitro and in vivo, and BRCA1-BARD1 co-expression in cells causes NPM stabilization rather than degradation. This is consistent with the notion that this ligase catalyzes untraditional polyubiquitin chains. Given the many overlapped functions between NPM and BRCA1, we propose that NPM is a strong candidate as a substrate of the BRCA1-BARD1 ubiquitin ligase.

Animals↗
PubMed2004

Fez1 is layer-specifically expressed in the adult mouse neocortex.

The mammalian cerebral neocortex occupies the largest area of the cerebral cortex and is cytoarchitectually composed of six layers (I-VI). Recent molecular analysis has begun to reveal the existence of various developmental programs, including the genetic regulation of arealization of the neocortex. Although an increasing number of molecular determinants of the developmental stages of the neocortex have been identified, no genes specifically expressed in the adult neocortex have been identified to date. By global screening using microarrays, combined with systematic in situ hybridization, we identified a zinc-finger type transcription factor, Fez1, which is expressed predominantly in the mouse adult neocortex. No other genes in the neocortex have been shown to date to have their expression with such high specificity. Using two-color in situ hybridization, we show that Fez1 is mainly expressed in cortical layers V and VI, not in gamma-aminobutyric acid neurons but in pyramidal neurons, the projection neurons of the cerebral cortex. Immunohistochemistry also shows that Fez1 is expressed in deep layers of the neocortex. Fez1 will be invaluable not only for the molecular understanding of corticogenesis but also for understanding the physiological functions of the adult neocortex, as well as for the use of its promoter in gene-manipulated animals and in conditional expression systems.

Animals↗
PubMed2004

Effects of psychotomimetic and antipsychotic agents on neocortical and striatal concentrations of various amino acids in the rat.

A subcutaneous injection of small and moderate doses (1.6, 3.2, 4.0 and 4.8 mg/kg) of the schizophrenomimetic methamphetamine caused a dose-related increase in the tissue content (the net content) of L-Arg and L-Asn in the neocortex and striatum at 60 min, but not at 360 min, after injection. The methamphetamine-induced (4.8 mg/kg) increases in levels of these amino acids were significantly attenuated by pretreatment with an antipsychotic drug, haloperidol (1 mg/kg) or clozapine (10 mg/kg). In the neocortex, a clozapine-reversible increase in the level of L-Thr was also observed 60 min after methamphetamine administration. Striatal concentrations of L-Glu, L-Ser, LThr, Gly and L-Ala were augmented by the same regimen in a haloperidol- and clozapine-sensitive fashion. A moderate dose of another schizophrenomimetic phencyclidine (7.5 mg/kg) given subcutaneously induced robust abnormal behavior, a diminution in the neocortical and striatal levels of L-Asp and an increase in the striatal L-Ala content without significant effects on the other amino acids studied. These results suggest that neocortical and striatal L-Arg, L-Asn, L-Thr, Gly, L-Ala or L-Ser may be implicated in the psychotomimetic effects of methamphetamine and might display mutual interaction with cerebral dopaminergic transmission. The differential effects of methamphetamine and phencyclidine on the net neocortical and striatal concentrations of various amino acids might, at least in part, underlie the distinct features of psychoses induced by these two drugs.

Amino Acids↗
PubMed2004

Case-control association study of human netrin G1 gene in Japanese schizophrenia.

The exact etiology of schizophrenia remains undetermined but accumulating evidence suggests that disturbances in neurodevelopment may represent one contributory factor. Netrin G1, a recently cloned gene from the mouse, has been shown to play a potential role in the formation of neural circuitry. To determine whether this gene is involved in the development of psychosis, we performed a genetic association study of human netrin G1 gene in schizophrenia. First, we determined the human genomic structure of netrin G1 by direct comparisons between cDNA and genome sequences, and by database searches. For the subsequent examination of heterozygosity, we selected 10 single nucleotide polymorphisms (SNPs) for an association test in case (n = 180) and control (n = 180) samples. Among these SNPs, IVS8-1467C>T showed significant allelic association (nominal P = 0.020) with disease. This SNP is located in a haplotype block of approximately 40 kb and haplotypes in this block also displayed significant association (most significant P = 0.017). These findings suggest that netrin G1 or a nearby gene may contribute to the overall genetic risk for schizophrenia.

Adult↗
PubMed2003

Differential regulation by stimulants of neocortical expression of mrt1, arc, and homer1a mRNA in the rats treated with repeated methamphetamine.

The present work was conducted to obtain clues for the possible roles of a novel stimulant-inducible gene mrt1 (methamphetamine-responsive transcript 1) encoding a PDZ-PX protein in stimulant-induced behavioral sensitization. In the young adult rats, repeated daily treatment with methamphetamine (4 mg/kg, intraperitoneally, once a day) for 5 days caused an enhanced behavioral response to methamphetamine: behavioral sensitization. The 5-day intermittent administration of MAP upregulated the basal expression of mrt1 transcripts and eliminated the increasing effects of a challenge dose of MAP (1.6 mg/kg, i.p.) or cocaine (30 mg/kg, i.p.) on mrt1 expression on day 14 of withdrawal in the neocortex that has been considered to be composed of a neuron circuit implicated in the sensitization phenomenon. In contrast, the basal expression of other stimulant-inducible and plasticity-related genes arc and homer1a and the ability of MAP or cocaine challenge to augment the amounts of their transcripts were not affected by the repeated MAP regimen in the cortical area. These findings suggest the differential regulation by stimulant of neocortical mrt1, arc, and homer1a expression in the behaviorally sensitized animals and supports the view that stimulant induction of mrt1 may be involved in the early molecular signalings for stimulant sensitization.

Animals↗