Effect of the CYP2D6 genotype on prolactin concentration in schizophrenic patients treated with haloperidol.
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Adult↗
Biomedical subjects
A Suzuki
Publications and source records attributed to A Suzuki.
First observation of clusters for solvated tropylium ions.
We have first observed clusters for solvated tropylium ions (Tr+(ROH)n) which were isolated from ROH-CH3CN (1:1 by vol.; R = Me, Et, and Prn) solutions by using a specially designed mass spectrometer and found the clear-cut essential features concerning the solvation structure around Tr+.
Journal Article↗
The stress kinase mitogen-activated protein kinase kinase (MKK)7 is a negative regulator of antigen receptor and growth factor receptor-induced proliferation in hematopoietic cells.
The dual specificity kinases mitogen-activated protein kinase (MAPK) kinase (MKK)7 and MKK4 are the only molecules known to directly activate the stress kinases stress-activated protein kinases (SAPKs)/c-Jun N-terminal kinases (JNKs) in response to environmental or mitogenic stimuli. To examine the physiological role of MKK7 in hematopoietic cells, we used a gene targeting strategy to mutate MKK7 in murine T and B cells and non-lymphoid mast cells. Loss of MKK7 in thymocytes and mature B cells results in hyperproliferation in response to growth factor and antigen receptor stimulation and increased thymic cellularity. Mutation of mkk7 in mast cells resulted in hyperproliferation in response to the cytokines interleukin (IL)-3 and stem cell factor (SCF). SAPK/JNK activation was completely abolished in the absence of MKK7, even though expression of MKK4 was strongly upregulated in mkk7(-/-) mast cell lines, and phosphorylation of MKK4 occurred normally in response to multiple stress stimuli. Loss of MKK7 did not affect activation of extracellular signal-regulated kinase (ERK)1/2 or p38 MAPK. mkk7(-/-) mast cells display reduced expression of JunB and the cell cycle inhibitor p16INK4a and upregulation of cyclinD1. Reexpression of p16INK4a in mkk7(-/-) mast cells abrogates the hyperproliferative response. Apoptotic responses to a variety of stimuli were not affected. Thus, MKK7 is an essential and specific regulator of stress-induced SAPK/JNK activation in mast cells and MKK7 negatively regulates growth factor and antigen receptor-driven proliferation in hematopoietic cells. These results indicate that the MKK7-regulated stress signaling pathway can function as negative regulator of cell growth in multiple hematopoietic lineages.
Animals↗
An AAV-derived Apaf-1 dominant negative inhibitor prevents MPTP toxicity as antiapoptotic gene therapy for Parkinson's disease.
Adeno-associated virus (AAV) vector delivery of an Apaf-1-dominant negative inhibitor was tested for its antiapoptotic effect on degenerating nigrostriatal neurons in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of Parkinson's disease. The wild-type caspase recruitment domain of Apaf-1 was used as a dominant negative inhibitor of Apaf-1 (rAAV-Apaf-1-DN-EGFP). An AAV virus vector was used to deliver it into the striatum of C57 black mice, and the animals were treated with MPTP. The number of tyrosine hydroxylase-positive neurons in the substantia nigra was not changed on the rAAV-Apaf-1-DN-EGFP injected side compared with the noninjected side. We also examined the effect of a caspase 1 C285G mutant as a dominant negative inhibitor of caspase 1 (rAAV-caspase-1-DN-EGFP) in the same model. However, there was no difference in the number of tyrosine hydroxylase-positive neurons between the rAAV-caspase-1-DN-EGFP injected side and the noninjected side. These results indicate that delivery of Apaf-1-DN by using an AAV vector system can prevent nigrostriatal degeneration in MPTP mice, suggesting that it could be a promising therapeutic strategy for patients with Parkinson's disease. The major mechanism of dopaminergic neuronal death triggered by MPTP seems to be the mitochondrial apoptotic pathway.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
Constitutive expression of hypoxia-inducible factor-1alpha renders pancreatic cancer cells resistant to apoptosis induced by hypoxia and nutrient deprivation.
Hypovasculature is an outstanding characteristic of pancreatic cancers in imaging diagnosis, suggesting that blood supply is poor in pancreatic cancer tissues. Despite poor blood supply, pancreatic cancer cells survive and proliferate in severe hypoxia and nutrient deprivation. To demonstrate how pancreatic cancer cells adapt themselves to hypoxia and nutrient deprivation, we investigated the expression of hypoxia-inducible factor 1alpha (HIF-1alpha) protein and HIF-1-inducible genes in human pancreatic cancer cell lines in comparison with other cancer cell lines. We found that HIF-1alpha protein was constitutively expressed in 15 of 20 pancreatic cancer cell lines (75%) but in none of other cancer cell lines tested in this study. The cells with constitutive expression of HIF-1alpha were more resistant to apoptosis induced by hypoxia and glucose deprivation than those without constitutive expression of HIF-1alpha. Transfection with HIF-1alpha transformed the latter cells resistant to apoptosis and increased in vivo tumorigenicity. Furthermore, anaerobic metabolism-associated genes, Glut1 and aldolase A, were more highly expressed in the cells with constitutive expression of HIF-1alpha than in the cells without it. These results suggest that constitutive expression of HIF-1alpha contributes to the survival and proliferation of pancreatic cancer cells in hypoxia and glucose deprivation through the activation of anaerobic metabolism.
Animals↗
The cell polarity protein ASIP/PAR-3 directly associates with junctional adhesion molecule (JAM).
The establishment and maintenance of cellular polarity are critical for the development of multicellular organisms. PAR (partitioning-defective) proteins were identified in Caenorhabditis elegans as determinants of asymmetric cell division and polarized cell growth. Recently, vertebrate orthologues of two of these proteins, ASIP/PAR-3 and PAR-6, were found to form a signalling complex with the small GTPases Cdc42/Rac1 and with atypical protein kinase C (PKC). Here we show that ASIP/PAR-3 associates with the tight-junction-associated protein junctional adhesion molecule (JAM) in vitro and in vivo. No binding was observed with claudin-1, -4 or -5. In fibroblasts and CHO cells overexpressing JAM, endogenous ASIP is recruited to JAM at sites of cell-cell contact. Over expression of truncated JAM lacking the extracellular part disrupts ASIP/PAR-3 localization at intercellular junctions and delays ASIP/PAR-3 recruitment to newly formed cell junctions. During junction formation, JAM appears early in primordial forms of junctions. Our data suggest that the ASIP/PAR-3-aPKC complex is tethered to tight junctions via its association with JAM, indicating a potential role for JAM in the generation of cell polarity in epithelial cells.
Adaptor Proteins, Signal Transducing↗
Probing the interaction of dengue virus envelope protein with heparin: assessment of glycosaminoglycan-derived inhibitors.
A structure-activity relationship study was carried out to facilitate development of inhibitors of dengue virus infectivity. Previous studies demonstrated that a highly charged heparan sulfate, a heparin-like glycosaminoglycan found on the cell surface, serves as a receptor for dengue virus by binding to its envelope protein. Interventions that disrupt this binding effectively inhibit infectivity. A competitive binding assay was developed to screen polyanionic compounds for activity in preventing binding of dengue virus envelope protein to immobilized heparin; compounds tested included drugs, excipients, and larger glycosaminoglycans and their semisynthetic derivatives. Results of this competitive binding assay were used to select agents for detailed evaluation of interactions by surface plasmon resonance spectroscopy, which afforded binding on-rates, off-rates, and dissociation constants. From these data, an understanding of the structural requirements for polyanion binding to dengue virus envelope protein has been established.
Anticoagulants↗
A novel integrin-linked kinase-binding protein, affixin, is involved in the early stage of cell-substrate interaction.
Focal adhesions (FAs) are essential structures for cell adhesion, migration, and morphogenesis. Integrin-linked kinase (ILK), which is capable of interacting with the cytoplasmic domain of beta1 integrin, seems to be a key component of FAs, but its exact role in cell-substrate interaction remains to be clarified. Here, we identified a novel ILK-binding protein, affixin, that consists of two tandem calponin homology domains. In CHOcells, affixin and ILK colocalize at FAs and at the tip of the leading edge, whereas in skeletal muscle cells they colocalize at the sarcolemma where cells attach to the basal lamina, showing a striped pattern corresponding to cytoplasmic Z-band striation. When CHO cells are replated on fibronectin, affixin and ILK but not FA kinase and vinculin concentrate at the cell surface in blebs during the early stages of cell spreading, which will grow into membrane ruffles on lamellipodia. Overexpression of the COOH-terminal region of affixin, which is phosphorylated by ILK in vitro, blocks cell spreading at the initial stage, presumably by interfering with the formation of FAs and stress fibers. The coexpression of ILK enhances this effect. These results provide evidence suggesting that affixin is involved in integrin-ILK signaling required for the establishment of cell-substrate adhesion.
Actinin↗
Molecular cloning and expression of a novel human beta-Gal-3-O-sulfotransferase that acts preferentially on N-acetyllactosamine in N- and O-glycans.
A novel cDNA-encoding galactose 3-O-sulfotransferase was cloned by screening the expressed sequence tag data base using the previously cloned cDNA encoding a galactosyl ceramide 3-O-sulfotransferase, which we term Gal3ST-1. The newly isolated cDNA encodes a novel 3-O-sulfotransferase, termed Gal3ST-3, that acts exclusively on N-acetyllactosamine present in N-glycans and core2-branched O-glycans. These conclusions were confirmed by analyzing CD43 chimeric proteins in Chinese hamster ovary cells expressing core2 beta1,6-N-acetylglucosaminyltransferase. The acceptor specificity of Gal3ST-3 contrasts with that of the recently cloned galactose 3-O-sulfotransferase (Honke, K., Tsuda, M., Koyota, S., Wada, Y., Iida-Tanaka, N., Ishizuka, I., Nakayama, J., and Taniguchi, N. (2001) J. Biol. Chem. 276, 267-274), which we term Gal3ST-2 in the present study because the latter enzyme can also act on core1 O-glycan and type 1 oligosaccharides, Galbeta1-->3GlcNAc. Moreover, Gal3ST-3 but not Gal3ST-2 can act on Galbeta1-->4(sulfo-->6)GlcNAc, indicating that disulfated sulfo-->3Galbeta1-->4(sulfo-->6) GlcNAc-->R may be formed by Gal3ST-3 in combination with GlcNAc 6-O-sulfotransferase. Although both Gal3ST-2 and Gal3ST-3 do not act on galactosyl ceramide, Gal3ST-3 is only moderately more homologous to Gal3ST-2 (40.1%) than to Gal3ST-1 (38.0%) at the amino acid level. Northern blot analysis demonstrated that transcripts for Gal3ST-3 are predominantly expressed in the brain, kidney, and thyroid where the presence of 3'-sulfation of N-acetyllactosamine has been reported. These results indicate that the newly cloned Gal3ST-3 plays a critical role in 3'-sulfation of N-acetyllactosamine in both O- and N-glycans.
Amino Acid Sequence↗
Expression of mouse igf2 mRNA-binding protein 3 and its implications for the developing central nervous system.
Functional analyses of neural RNA-binding proteins have focused mainly on their roles as modulators of posttranscriptional gene regulation, e.g., alternative splicing, dendritic mRNA localization, and local translation. Here we identified a mouse homologue of human IMP3, which is known to bind to and repress the translation of igf2 leader 3 mRNA. The mouse igf2 mRNA-binding protein 3 (mIMP3) is a member of the zipcode binding protein-1 (ZBP-1) family previously reported in chick fibroblast cells. mIMP3 was expressed in undifferentiated neuroepithelial cells and some postmitotic neurons at early embryonic stages (E10.5--E12.5), and its expression level decreased after the midembryonic stage (E12.5) until birth. The expression profile of mIMP3 is very similar to that of mouse igf2 leader 3 mRNA. In vitro UV cross-linking experiments showed that mIMP3 preferentially bound to igf2 leader 3 mRNA rather than igf2 leader 4 mRNA and did not bind the zipcode region of beta-actin or c-myc mRNA. Furthermore, persistent expression of mIMP3 protein in an undifferentiated P19 cell line revealed that mIMP3 inhibited neuronal differentiation morphologically and immunohistochemically. Taken together, these observations raise the possibility that mIMP3 represses neuronal differentiation through the regulation of igf2 mRNA expression.
5' Untranslated Regions↗
Frequent association between trisomy 15 and t(8;21)(q22;q22) in acute myeloid leukemia.
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Acute Disease↗
Relationship between Taq1 A dopamine D2 receptor (DRD2) polymorphism and prolactin response to bromperidol.
The dopamine D2 receptor (DRD2) gene has a Taq1 A restriction fragment length polymorphism yielding two alleles, A1 and A2. We have previously shown that female patients with the A1 allele show greater prolactin response to nemonapride, a selective antagonist for D2-like dopamine receptors, in schizophrenic patients. In the present study, the relationship between this polymorphism and prolactin response to bromperidol was investigated in 32 untreated schizophrenic inpatients (16 males, 16 females). The daily dose of bromperidol was fixed at 6 (n = 10), 12 (n = 13), or 18 mg (n = 9) during a 2-week treatment period. Taq1 A genotypes were determined by PCR method. Plasma prolactin concentration was measured by radioimmunoassay. Plasma concentration of bromperidol was measured by HPLC method. The subjects were divided into four subgroups by gender and the genotypes, i.e., 10 males and 11 females with the A1 allele, 6 males and 5 females with no A1 allele. The females with the A1 allele had the highest Delta prolactin (the change from the pretreatment concentration)/bromperidol concentration ratio among the other groups (P < 0.05). The present study thus suggests that female patients with the A1 allele show greater prolactin response to bromperidol, who may have a high risk for adverse effects associated with neuroleptic-induced hyperprolactinemia.
Adult↗
Cloning and expression of a down-regulated gene (TrEnodDR1) of white clover responded by the nod genes derived from Rhizobium leguminosarum bv. trifolii strain 4S.
The nodulation genes of Rhizobium leguminosarum bv. trifolii 4S (strain 4S) were cloned into cosmid vector pLAFR1 named pC4S8 which was contained nodNMLFEDABCIJ and a part of nodT as an insert. The pC4S8 was transferred to strain H1, Sym plasmid (pRt4Sa) cured strain of strain 4S, and isolated as Tc resistant and nodulation restored mutant, strain H1(pC4S8). During infection process of this strain, visible symbiotic features, such as root hair curling (Hac), root hair deformation (Had) and infection thread formation (Inf) were also restored. The nodule forming ability of strain H1(pC4S8) was increased 3-4 times in nodule number than that of strain 4S. Then, to investigate the effect of Rhizobium nod genes on the host plant (Trifolium repens L.) gene expression, cDNAs which were responded to the inoculation of rhizobia were differentially screened based on the presence or absence of nod genes treated with strains H1(pC4S8) or H1, respectively. The cDNA, TrEnodDR1 (Trifolium repens early nodulin down regulation 1) gene was isolated from cDNA library prepared from white clover seedlings treated with nod- strain H1, but didn't exhibit in nod+ treated cDNA library, as a down-regulated gene. Expression analysis of TrEnodDR1 was performed in various tissues of white clover, it is suppressed in root nodule and also strongly suppressed by the inoculation of rhizobia in the seedlings. It is discussed that TrEnodDR1 gene is suppressed when the white clover comes into symbiosis with rhizobia.
Amino Acid Sequence↗
Atypical protein kinase C is involved in the evolutionarily conserved par protein complex and plays a critical role in establishing epithelia-specific junctional structures.
We have previously shown that during early Caenorhabditis elegans embryogenesis PKC-3, a C. elegans atypical PKC (aPKC), plays critical roles in the establishment of cell polarity required for subsequent asymmetric cleavage by interacting with PAR-3 [Tabuse, Y., Y. Izumi, F. Piano, K.J. Kemphues, J. Miwa, and S. Ohno. 1998. Development (Camb.). 125:3607--3614]. Together with the fact that aPKC and a mammalian PAR-3 homologue, aPKC-specific interacting protein (ASIP), colocalize at the tight junctions of polarized epithelial cells (Izumi, Y., H. Hirose, Y. Tamai, S.-I. Hirai, Y. Nagashima, T. Fujimoto, Y. Tabuse, K.J. Kemphues, and S. Ohno. 1998. J. Cell Biol. 143:95--106), this suggests a ubiquitous role for aPKC in establishing cell polarity in multicellular organisms. Here, we show that the overexpression of a dominant-negative mutant of aPKC (aPKCkn) in MDCK II cells causes mislocalization of ASIP/PAR-3. Immunocytochemical analyses, as well as measurements of paracellular diffusion of ions or nonionic solutes, demonstrate that the biogenesis of the tight junction structure itself is severely affected in aPKCkn-expressing cells. Furthermore, these cells show increased interdomain diffusion of fluorescent lipid and disruption of the polarized distribution of Na(+),K(+)-ATPase, suggesting that epithelial cell surface polarity is severely impaired in these cells. On the other hand, we also found that aPKC associates not only with ASIP/PAR-3, but also with a mammalian homologue of C. elegans PAR-6 (mPAR-6), and thereby mediates the formation of an aPKC-ASIP/PAR-3-PAR-6 ternary complex that localizes to the apical junctional region of MDCK cells. These results indicate that aPKC is involved in the evolutionarily conserved PAR protein complex, and plays critical roles in the development of the junctional structures and apico-basal polarization of mammalian epithelial cells.
Actins↗
Polar alteration of short tandem repeats (STRs) in mammalian cells.
Instability of short tandem repeats (STRs) in DNA during replication is observed in all organisms examined, and is causatively involved in various human diseases. We explore the mechanisms involved in instability by examining length changes occurring during the replication of [(CA)(20)TA](n) and [(CAG)(20)TAG](n), in human cells. We show that the majority of alterations consist of an insertion or deletion of one repeat unit, and base substitutions or length changes involving many repeat units are rare. We also show that length changes of two-tract STRs are biased toward the 3'-end of the repeat tract, in reference to lagging strand synthesis. There are some differences between our observations and previous observations in microbes, e.g. the orientation effect was not observed in this study. The results of this study are discussed in terms of the molecular mechanisms leading to alterations in repeat tracts.
Animals↗
DXAFS study on the decarbonylation process of Mo(CO)6 in NaY supercages.
The decarbonylation process of Mo(CO)6 in the NaY supercages was studied by means of a time resolved dispersive XAFS method during temperature programmed decarbonylation. XANES analysis demonstrated that the decarbonylation proceeded through two steps and that a stable intermediate existed between 440-490 K. The curve fitting analysis revealed that the intermediate was a molybdenum monomer subcarbonyl species coordinated by three CO ligands and three oxygen atoms of zeolite framework. Molybdenum dimer subcarbonyl species were not observed. This study demonstrated that DXAFS technique is a powerful method to study the dynamic behaviour of the Mo carbonyl species during decarbonylation process.
Journal Article↗
CIS3/SOCS3/SSI3 plays a negative regulatory role in STAT3 activation and intestinal inflammation.
Immune and inflammatory systems are controlled by multiple cytokines, including interleukins (ILs) and interferons. These cytokines exert their biological functions through Janus tyrosine kinases and signal transducer and activator of transcription (STAT) transcription factors. We recently identified two intrinsic Janus kinase (JAK) inhibitors, JAK binding protein (JAB; also referred to as suppressor of cytokine signaling [SOCS1]/STAT-induced STAT inhibitor [SSI1]) and cytokine-inducible SH2 protein (CIS)3 (or SOCS3/SSI3), which play an essential role in the negative regulation of cytokine signaling. We have investigated the role of STATs and these JAK inhibitors in intestinal inflammation. Among STAT family members, STAT3 was most strongly tyrosine phosphorylated in human ulcerative colitis and Crohn's disease patients as well as in dextran sulfate sodium (DSS)-induced colitis in mice. Development of colitis as well as STAT3 activation was significantly reduced in IL-6-deficient mice treated with DSS, suggesting that STAT3 plays an important role in the perpetuation of colitis. CIS3, but not JAB, was highly expressed in the colon of DSS-treated mice as well as several T cell-dependent colitis models. To define the physiological role of CIS3 induction in colitis, we developed a JAB mutant (F59D-JAB) that overcame the inhibitory effect of both JAB and CIS3 and created transgenic mice. DSS induced stronger STAT3 activation and more severe colitis in F59D-JAB transgenic mice than in their wild-type littermates. These data suggest that hyperactivation of STAT3 results in severe colitis and that CIS3 plays a negative regulatory role in intestinal inflammation by downregulating STAT3 activity.
Animals↗
MDM2 enhances the function of estrogen receptor alpha in human breast cancer cells.
Overexpression of the oncoprotein MDM2, a negative feedback regulator of p53, is often observed in breast cancer tissue and cell lines, particularly in those which express estrogen receptor alpha (ERalpha). In this study, we report a novel function of MDM2, i.e., as a positive regulator of ERalpha. This function does not involve p53. MDM2 overexpressing clones derived from the breast cancer cell line, MCF-7 cells, showed a remarkable growth advantage only in estradiol supplemented conditions, and this profile coincided with increased transcriptional activity of ERalpha in these cells. Though p53 has been reported to be an inhibitor of ERalpha function, p53 protein in MDM2 overexpressing clones was more abundant than in the parental cells. When ERalpha was exogenously expressed in p53-null cells, its activity was enhanced by coexpression of MDM2. Mammalian two-hybrid assays and GST pull-down assays indicated that MDM2 could interact with ERalpha. These results indicate that MDM2 is a direct activator of ERalpha function, and suggest such a role for MDM2 in ERalpha-positive breast cancer.
Blotting, Western↗